Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Benjamin J. Gosney
  • Christian R. Robinson
  • Venkateswarlu Kanamarlapudi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_609


Historical Background

ADAP1 (ADP-ribosylation factor [ARF] GTPase activating protein [GAP] with dual pleckstrin homology (PH) domains 1) was initially characterized from pig cerebellum and identified as a 42 kDa protein that binds with high affinity to phosphatidylinositol (3,4,5)-triphosphate (PIP3) or its inositol head group, inositol 1,3,4,5-tetrakisphosphate (IP4) (Reiser et al. 1991). Hence, it was originally named PIP3/IP4-binding protein (PIP3BP/p42IP4) and has also been called Centaurin-α1 (Hammonds-Odie et al. 1996; Stricker et al. 1997; Tanaka et al. 1999). It has been renamed ADAP1, which more accurately describe the structure and function of this protein (Kahn et al. 2008). The membrane lipid PIP3 and the water-soluble ligand IP4 both serve as signal transducers that link extracellular stimuli to numerous intracellular signaling cascades required for cell growth, multiplication, differentiation, and death (Vanhaesebroeck et al. 2001; Hanck et al. 2004). ADAP1 contains an amino-terminal zinc-finger motif with an ARF GAP homology domain and two adjacent PH domains (one in the middle [PH1] and the other at the carboxy terminus [PH2]) that are required for binding to PIP3 (see Fig. 1). It has high sequence similarity to the Centaurin-α2 protein, with 58% amino-acid identity and 75% similarity (Whitley et al. 2002; Hanck et al. 2004). The ADAP1 gene is located on human chromosome 7p22.3 (Hanck et al. 2004).
ADAP1, Fig. 1

Schematic representation of human ADAP1 splice variants

Protein Function and Regulation of Activity

ADAP1 has both GAP domain-dependent and domain-independent effects. The rat homolog was shown to have a role in dendritic density and branching in a GAP domain-dependent manner. Dendritic lamellipodia and filopodia have been implicated in dendritic branching and spine formation, and the same study demonstrated that ADAP1 plays a part in their formation; this effect was again dependent on the GAP domain (Moore et al. 2007). In HeLa cells, human ADAP1 prevents cortical actin reorganization, which was shown to be a consequence of its GAP activity toward the ARF6 small GTPase (Venkateswarlu et al. 2004). Additionally, it has been shown that cotransfection of HEK293 with ADAP1 and the β2 adrenoceptor leads to a decrease in the receptor internalization and an increase in Gαs signaling (Lawrence et al. 2005); this effect was the GAP domain dependent.

Cell spreading is a GAP domain-independent effect of ADAP1. Intriguingly, the expression of a ΔGAP mutant, which lacks the GAP domain, of ADAP1 has increased cell spreading, suggesting that the interaction of ADAP1 with ARF6 may decrease this effect. This function might be linked to its colocalization with the ARF5 and ARF6 small GTPases (Thacker et al. 2004). Other studies unconcerned with its GAP activity found that ADAP1 induces the downstream activation of ERK1/2 and Elk-1 through a phosphatidylinositol 3-kinase (PI3K)-dependent pathway (Hayashi et al. 2006), and infection of chick embryonic fibroblasts with retrovirus encoding ADAP1 led to anchorage-independent proliferation at an increased rate through adaptor protein-1 (AP-1) activation (Chanda et al. 2003), suggesting that ADAP1 could have oncogenic potential. Mitochondria isolated from neuroblastoma cells that overexpress ADAP1 showed significantly decreased Ca2+ capacity and lag time for Ca2+ retention, suggesting that ADAP1 is involved in the regulation of mitochondrial Ca2+ transport (Galvita et al. 2009).

Amyloid-β peptide (derived from β-amyloid precursor protein [APP]), which is involved in plaque formation during Alzheimer’s disease, has shown to enhance ADAP1 expression by 2.5-fold within 48 h of incubation in hippocampal neurons and organotypic hippocampal slices (Szatmari et al. 2013). ADAP1 is also known to increase the levels of amyloid-β peptide. Amyloid-β also induces the Elk-1 translocation to mitochondria in an ADAP1-dependent manner. Similar effects are observed in a mouse model of Alzheimer’s disease (APP mice), leading to downstream Ras-Elk-1 signaling at mitochondria, impaired mitochondrial functions, reduced spine density and synaptic dysfunction, and intensified neurodegeneration (Szatmari et al. 2013). In the APP mice, enhanced levels of ADAP1 and mitochondrial translocation of Elk-1 occur at the age of 6 months. By 12 months, both ADAP1 and Elk-1 expression decay but the phenotype continues, suggesting that ADAP1-Ras-Elk-1 signaling at mitochondria in neural cells occurs at an early stage of Alzheimer’s disease. A downregulation of ADAP1-induced Ras-Elk-1 signaling is seen to reverse this phenotype (Szatmari et al. 2013).

In unstimulated PC12 cells, ADAP1 localizes to the cytoplasm and nucleus. Upon stimulation of PC12 cells with EGF, ADAP1 translocates to the plasma membrane. This has been shown to be dependent on a PI3K-induced increase of PIP3 at the plasma membrane, which binds to the PH domains of ADAP1 (Venkateswarlu and Cullen 1999; Venkateswarlu et al. 1999). The translocation was shown to be abrogated in HEK293 by pretreatment with thrombin, an effect that was exacerbated by increasing the intracellular IP4 pool using LiCl (Sedehizade et al. 2005). As thrombin acts through a Gq-linked G-protein-coupled receptor (GPCR), it is possible that other Gq-linked GPCRs may have a similar effect.

The activated ARF6, ARF6-GTP, is responsible for regulating epithelial cell-cell junctions by maintaining E-cadherin expression and controlling clathrin-dependent endocytosis. This process is inactivated by ADAP1, thus, regulating the apical-basal polarity. ADAP1 inactivates ARF6 to internalize E-cadherin and result in degradation of adherence junctions to confer cell migratory properties. ADAP1 is also responsible for transporting cargo and regulating actin networks for focal adhesions (Schweitzer et al. 2011; Pellon-Cardenas et al. 2013). In vitro binding between ADAP1 and actin has also been demonstrated (Thacker et al. 2004). Actin binding is mediated through its PIP3-binding PH domain(s), similar to that shown for Bruton’s tyrosine kinase (BTK).

Interestingly, ADAP1 also localizes at sites of internalization during bacterial infection (Davidson et al. 2015). The colocalization of ARF6 and ADAP1 at the plasma membrane promotes recycling of macropinosomes to the plasma membrane, which are then used by extracellular Salmonella to aid further infection into the cell. Salmonella uses ARF6/ADAP1 cycling to its advantage and controls ARF6 activation by disrupting the host GEFs, thus, driving cytoskeletal remodeling and infection. However, ARF6 dysfunction and reduced levels of ADAP1 impair the recycling by reducing the active ARF6 levels to inhibit further infection (Davidson et al. 2015), highlighting the importance of ARF6 inactivation during micropinocytosis. Further studies with Y. enterocolitica highlight the recruitment of ADAP1 in the PI3K pathway for bacterial cell entry (Dowd et al. 2016). Bacterial Ivasin- or InlB-mediated uptake requires ADAP1 at the plasma membrane, which is responsible for F-actin accumulation and actin cytoskeleton remodeling to aid internalization during infection.

As mentioned above, ADAP1 is an inositol phosphate–binding protein, which binds to its ligands, the membrane-bound PIP3 and the cytosolic IP4, with similar affinities (Stricker et al. 1997; Tanaka et al. 1999; Venkateswarlu and Cullen 1999; Venkateswarlu et al. 1999). It also binds to phosphatidylinositol(3,4)-bisphosphate (PI(3,4)P2) (Rao et al. 1999; Kalscheuer et al. 2009).

KIF13B was identified as an ADAP1-binding partner in a yeast two-hybrid screen (Venkateswarlu et al. 2005). KIF13B contains an N-terminal motor domain, a large stalk domain at the center, and the CAP-GLY domain (a putative microtubule interacting sequence) at the C terminus. ADAP1 directly interacts with the stalk domain of KIF13B through its GAP domain and this interaction is essential to maintain its localization at the leading edges of the cell. Moreover, KIF13B negatively regulates the GAP activity of ADAP1 in vivo. Together, these studies suggest that an ADAP1–KIF13B complex may provide a means for concentrating ADAP1 at the leading edges of the cell, where it regulates ARF6 activity (Kanamarlapudi 2005; Venkateswarlu et al. 2005). These findings also raise the possibility that KIF13B both temporally and spatially regulates the activity of ARF6. Moreover, the ADAP1–KIF13B complex transports PIP3 to the neurite ends in neurons and thereby regulates the establishment of neuronal polarity (Horiguchi et al. 2006).

Several PKC isoforms (PKCα, λ, μ, and ζ) bind to ADAP1 in vitro by their cysteine-rich C1 domain, as demonstrated through affinity chromatography and GST pull-down assays (Zemlickova et al. 2003). This interaction results in phosphorylation of Centaurin-α1 at Ser87 in the GAP domain and Thr276 in the C-PH domain.

ADAP1 has also been shown to bind to the scaffolding protein RanBPM (Ran binding protein in the microtubule-organizing center) in vitro and in vivo by the SPRY domain of RanBPM and the ARF GAP domain of ADAP1. The association between these two proteins is inhibited by the ADAP1 ligand IP4 (Haase et al. 2008).

ADAP1 also associates with casein kinase I (CKI) isoforms α, δ, ε, λ1, λ2, and λ3 but there is no evidence to suggest that this interaction modulates the activity of either ADAP1 or CKI, so it is difficult to assign a function to this protein–protein interaction (Dubois et al. 2002). It has been suggested that ADAP1 may act as an adaptor protein for CKI lipid binding (Dubois et al. 2002). It is also possible that the ADAP1–CKI interaction has a role in the etiology of Alzheimer’s disease due to an established role for CKI in disease pathology and an increased expression of ADAP1 in patients with Alzheimer’s disease (Reiser and Bernstein 2002). Consistent with this, ADAP1 has been implicated in Alzheimer’s disease (Szatmari et al. 2013).

ADAP1 binds to the metalloendopeptidase NRDc (N-arginine dibasic convertase; also known as nardilysin) (Stricker et al. 2006). In the human brain, considerable overlap was found between ADAP1 and nardilysin (NRDc) expression. In the hypothalamic paraventricular nucleus (PVN), about two-thirds of ADAP1-immunoreactive neurons coexpress NRDc, whereas 80% of the NRDc-containing neurons did costain for ADAP1 (Bernstein et al. 2007). The proteins ADAP1 and nardilysin dissociate from each other in the presence of IP4, but not of Inositol 1,4,5-trisphosphate (IP3) (Stricker et al. 2006). The ligand interaction of ADAP1 is stereospecific (Stricker et al. 1996). Once bound, ADAP1 positively modulates NRDc by enhancing the enzymatic activity three- to fourfold. In SH-SY5Y cells (a human neuroblastoma cell line), NRDc expression is upregulated sixfold after 15 days incubation with retinoic acid, whereas ADAP1 levels remain undetectable. Interestingly, retinoic acid upregulates NRDc expression within 6 days of incubation in ADAP1 transfected cells (Borrmann et al. 2011a). This ADAP1-dependent upregulation of NRDc expression may suggest a link between the expression of NRDC and functional relevance of NRDc and ADAP1 interaction during development. Moreover, ADAP1-transfected SH-SY5Y cells exhibit colocalization of ADAP1, NRDc, and tubulin at the plasma membrane and in the cytosol. ADAP1 alone interacts with α-tubulin at the plasma membrane and NRDc with β-tubulin. Enhancement of ADAP1 and NRDc interactions by tubulin, together with known ADAP1 and F-actin interactions, suggests a possible link between both actin and tubulin networks (Borrmann et al. 2011b). However, further research is needed to identify the function of ADAP1 localization to actin and tubulin networks. ADAP1 interacting motor protein KIF13b, which also interacts with microtubules and actin, regulates neuronal cell myelination (Noseda et al. 2016). ADAP1 may, therefore, play a role in myelination and tubulin polymerization in neural cells, where disturbance of its expression results in the development of neurodegenerative diseases.

In a study investigating nuclear-located binding proteins for ADAP1, nucleolin (which is also involved in the pathology of Alzheimer’s disease (Reiser and Bernstein 2004)), the DNA-binding protein Pur-α, and the cerebellar leucine-rich acidic nuclear protein (LANP) were found to be ADAP1-interacting proteins. At lower concentrations, RNA polymerase II transcription cofactor 4 (mediator of RNA polymerase II transcription, subunit 8 (Med8)), the splicing factor arginine/serine-rich 2 (SFRS2), the pre-mRdNA splicing factor SF3, the β2 subunit of the adaptor-related protein complex 3, and the protein similar to ribosomal protein S9 were shown to interact with ADAP1 (Dubois et al. 2003).

Major Sites of Expression and Subcellular Localization

ADAP1 is abundantly expressed in the brain. It is also expressed at very low levels in nonneuronal tissues, such as spleen, lung, kidney, peripheral blood leukocytes, and retina (Hammonds-Odie et al. 1996; Stricker et al. 1997; Venkateswarlu and Cullen 1999). In the brain, ADAP1 was found in neurons of the cortex, hypothalamus, and hippocampus (Sedehizade et al. 2002; Moore et al. 2007). SH-SY5Y neuronal cell line has been used to study the effects of ADAP1 expression and localization in vitro (Borrmann et al. 2011a; Borrmann et al. 2011b; Szatmari et al. 2013).

Developmental expression analysis of ADAP1 in rodent brains revealed that its expression is detectable as early as embryonic day 16 and peaks between 2 weeks and 4 weeks postnatally (Aggensteiner and Reiser 2003; Moore et al. 2007).

In the rat brain, high levels of developmentally regulated ADAP1 expression are found in cerebellum, hippocampus, cortex, and thalamus (Kreutz et al. 1997a). In adults, the immunoreactivity is localized in most neuronal cell types and probably also in some glial cells. Prominent immunoreactivity is found in axonal processes and in cell types with long neurites. In the hypothalamus, a subpopulation of parvocellular neurons in the peri- and paraventricular nuclei is heavily labeled. This is confined by strong immunoreactivity in the lamina externa of the median eminence in close proximity to portal plexus blood vessels. Electron microscopy shows that ADAP1 protein is frequently associated with presynaptic vesicular structures (Kreutz et al. 1997a).

ADAP1 expression is upregulated in neurons in the brain of patients with Alzheimer’s disease (Reiser and Bernstein 2002, 2004). In rats, after acoustic and electric fear stimulation (startle response), the mRNA and protein levels were downregulated within 2 h in the amygdala, hypothalamus, and cingulate/retrosplenial cortex. ADAP1 mRNA decreased by about 50% for about 24 h (Reiser et al. 2004). There were characteristic changes of ADAP1 expression during development in the rat brain (Aggensteiner and Reiser 2003). The levels of ADAP1 mRNA were quantified at 7, 14, and 21 days of age, as well as in various brain regions of adult rats, including the cerebellum, cortex, striatum, thalamus, hypothalamus, olfactory bulb, hippocampus, and tectum (superior and inferior colliculus).

In rat, porcine, and bovine retina, ADAP1 is localized by in situ hybridization in the ganglion cell layer, the inner nuclear cell layer, and the outermost part of the outer nuclear cell layer (Kreutz et al. 1997b). Wide-field amacrine and retinal ganglion cells are intensely immunostained. Prominent immunoreactivity in the on/off sublaminae of the inner plexiform layer and in the optic nerve layer indicates a pre- and/or postsynaptic localization of the protein. Moreover, there is significant ADAP1 protein expression in the inner segment of photoreceptors. The end-feet of Müller glial cells in the optic nerve layer are also stained (Kreutz et al. 1997b).

ADAP1 and KIF13B/GAKIN colocalize after transfection of tagged proteins at the tip of growing neurites in PC12 cells. In cultured hippocampal neurons, endogenous ADAP1 is localized in growth cones (Horiguchi et al. 2006).

ADAP1 localizes to the cytoplasm and nucleus (Tanaka et al. 1999; Venkateswarlu et al. 1999). In polarized cells such as neurons, ADAP1 also localizes to dendrites, dendritic spines, and the postsynaptic region (Moore et al. 2007). ADAP1 is also found in mitochondria, where it regulates calcium levels (Galvita et al. 2009).

Phenotypes and Splice Variants

No studies on the phenotypic effects of ADAP1 have been carried out due to the lack of ADAP1-knockout mice. However, knockdown of Centaurin-α1 by short interfering RNA in cultured hippocampal neurons inhibits dendritic branching and length (Moore et al. 2007) and in HEK cells results in a reduction of EGF-stimulated ERK activation (Hayashi et al. 2006). In yeast, the deletion of the gene encoding the ADAP1 homolog, Gcs1, has been shown to hypersensitize the mutant to sodium fluoride. This effect can be rescued through introduction of human ADAP1 into gcs1 deleted yeast (Venkateswarlu et al. 1999).

Although there is no evidence so far for the expression of splice variants, northern analysis of rat brain Centaurin-α (renamed as “ADAP”) revealed a major transcript at 2.5 kb and a minor one at 4.0 kb (Hammonds-Odie et al. 1996). Both ADAP and ADAP1 were cloned from a rat brain cDNA library (Hammonds-Odie et al. 1996; Aggensteiner et al. 1998). ADAP is highly homologous to ADAP1 but contains a 43 amino-acid C-terminal extension and lacks the N-PH domain due to three frame-shift mutations in the cloned cDNA. However, ADAP has not been detected thus far by RT-PCR or immunoblotting, and therefore it is not yet possible to say whether ADAP is a splice variant of ADAP1 or not (Aggensteiner et al. 1998).

ADAP1 has four isoforms in humans (Fig. 1), with isoform 1 representing the predominant transcript. Isoform 2 contains an additional 5′ terminal exon and is the longest of the homologs. However, isoform 3 contains a shorter N-terminus, and isoform 4 lacks two exons at its 5′ end; resulting in shorter isoforms. These differences result in translation initiation from alterative start codons. The ADAP1 clone was corrected later (Thacker et al. 2004). Resequencing the original cDNA clone revealed two sequencing errors in the original submission (accession number U51013). Species comparisons with the revised rat sequence indicated that rat ADAP1 is the ortholog of human and murine ADAP1, porcine p42IP4, and bovine PIP3BP. Immunoblot analysis of endogenous rat brain ADAP1 demonstrated that it migrates as a doublet, but the basis for the difference in molecular mass has not yet been determined (Moore et al. 2007).

Hammonds-Odie and coworkers raised rabbit polyclonal antibodies against a 19-amino-acid peptide (AGELRRALLELLTRPGNSR) from the N-terminal end of rat Centaurin-α and against a C-terminal fusion protein. These antibodies are used in Western blotting applications for the detection of Centaurin-α (Hammonds-Odie et al. 1996). The Reiser group has produced its own anti-p42IP4 rabbit polyclonal and mouse monoclonal antibody, raised against a peptide consisting of amino acids 353–371 of pig ADAP1, and used it to detect human, pig, and rat ADAP1 by Western blot and immunohistochemistry (Kreutz et al. 1997a; Stricker et al. 1997; Aggensteiner et al. 1998; Reiser and Bernstein 2002; Sedehizade et al. 2002; Aggensteiner and Reiser 2003; Stricker et al. 2003, 2006). There are also several anti-Cetaurin-α1 antibodies that are commercially available. By far, the most widely used commercially available antibody against ADAP1 is a mouse monoclonal (P421; IgG1 subtype) raised against full-length pig ADAP1. This antibody is available from Santa Cruz Biotech (sc-51836), Abcam (ab10168), and HyTest Ltd. (4MA10) and has been used for detection of ADAP1 from human and pig by ELISA and Western blotting (Thacker et al. 2004; Venkateswarlu et al. 2005; Hayashi et al. 2006).

A goat anti-ADAP1 polyclonal antibody, raised against the synthetic peptide CQEYAVEAHFKHKP, which corresponds to amino acids 362–374 of human ADAP1, is available from Abcam (ab27476), Everest Biotech (EB06120), and Biorbyt (orb332484). This antibody can be used in ELISA, immunoctyochemistry, immunohistochemistry, and Western blotting applications to detect human, rat, and mouse ADAP1 (Moore et al. 2007).

A mouse polyclonal antibody, raised against the full-length human ADAP1 protein, is available from Novus Biologicals (H00011033-B01). This antibody is useful for detecting human ADAP1 by ELISA, Western blot, and immunofluoresence. A rabbit anti-ADAP1 antibody generated against GST-fused full-length human ADAP1 is available from Proteintech Group (13911-1-AP) and can be used to detect human and mouse ADAP1 by Western blot and immunohistochemistry.

A rabbit polyclonal antibody to human ADAP1 is available from LifeSpan Biosciences, Inc. (LS-C375143) with specificity for amino acids 1–364, useful for immunohistochemistry and ELISA. A rabbit polyclonal antibody to human ADAP1 is also available from Atlas Antibodies (HPA007033), St John’s Laboratory (STJ22512), and Abbexa (abx003351) useful for immunohistochemistry as well as for Western blotting and immunocytochemistry, with an antigen sequence identity of 94% to mouse and rat. A chicken polyclonal antibody (IgY) to human ADAP1, raised against the sequence C-z-QEYAVEAHFKHKP, is commercially available from Biorbyt (orb316166) and MyBioSource (MBS594005). This antibody is useful for Western blotting and is cross reactive against mouse and rat ADAP1.


ADAP1 (also known as Centaurin-α1/PIP3BP/p42IP4) is a PIP3/IP4-binding protein that regulates actin cytoskeleton organization and membrane trafficking by acting as a GAP for ARF6. The binding is stereospecific for IP4 (or PIP3) as it does not bind to IP3. It also associates with CKIα, RanBPM, nardilysin, the kinesin motor proteinKIF13B, PKC, and nucleolin. ADAP1 localization and activity have been shown to be regulated by PI3K, PKC isoforms, and KIF13B. It is abundantly expressed in brain tissue and is also detected in nonneuronal tissues at very low concentrations. ADAP1 expression is upregulated in neurons in the brain of patients with Alzheimer’s disease and is detected in amyloid plaques, indicating that it may be involved in neuronal diseases. ADAP1 is normally localized in the cytoplasm, nucleus, and mitochondria and it translocate to the plasma membrane by binding to PIP3 produced by agonist-activated PI3K to act as a GAP for ARF6. ADAP1 is responsible for maintaining apical-basal polarity by regulating E-cadherin expression and cell-cell junctions. ADAP1 localizes to dendritic spines and synapses in neurons and can affect differentiation, PIP3 transport, and vesicle secretion. It has also been implicated in regulation of Ca2+ transport in mitochondria and bacterial-mediated uptake during infection. There is no information on ADAP1-null phenotypes in mammals, but due to its putative role in neuronal development, it is possible that loss of ADAP1 may affect the viability of the organism. There are no known polymorphisms of the ADAP1 gene.


  1. Aggensteiner M, Reiser G. Expression of the brain-specific membrane adapter protein p42IP4/centaurin alpha, a Ins(1,3,4,5)P4/PtdIns(3,4,5)P3 binding protein, in developing rat brain. Brain Res Dev Brain Res. 2003;142:77–87.CrossRefPubMedGoogle Scholar
  2. Aggensteiner M, Stricker R, Reiser G. Identification of rat brain p42(IP4), a high-affinity inositol(1,3,4, 5)tetrakisphosphate/phosphatidylinositol(3,4,5)trisphosphate binding protein. Biochim Biophys Acta. 1998;1387:117–28.CrossRefPubMedGoogle Scholar
  3. Bernstein HG, Stricker R, Dobrowolny H, Trübner K, Bogerts B, Reiser G. Histochemical evidence for wide expression of the metalloendopeptidase nardilysin in human brain neurons. Neurobiologia. 2007;146:1513–23.Google Scholar
  4. Borrmann C, Stricker R, Reiser G. Retinoic acid-induced upregulation of the metalloendopeptidase nardilysin is accelerated by co-expression of the brain-specific protein p42IP4 (centaurin α1; ADAP1) in neuroblastoma cells. Neurochem Int. 2011a;59:936–44.CrossRefPubMedGoogle Scholar
  5. Borrmann C, Stricker R, Reiser G. Tubulin potentiates the interaction of the metalloendopeptidase nardilysin with the neuronal scaffold protein p42IP4/centaurin-α1 (ADAP1). Cell Tissue Res. 2011b;346:89–98.CrossRefPubMedGoogle Scholar
  6. Chanda SK, White S, Orth AP, Reisdorph R, Miraglia L, Thomas RS, et al. Genome-scale functional profiling of the mammalian AP-1 signaling pathway. Proc Natl Acad Sci U S A. 2003;100:12153–8.PubMedCentralCrossRefPubMedGoogle Scholar
  7. Davidson AC, Humphreys D, Brooks ABE, Hume PJ, Koronakis V. The Arf GTPase-activating protein family is exploited by salmonella enterica Serovar Typhimurium to invade nonphagocytic host cells. mBio. 2015;6:e02253–14.PubMedCentralCrossRefPubMedGoogle Scholar
  8. Dowd GC, Bhalla M, Kean B, Thomas R, Ireton K. Role of host type IA phosphoinositide 3-kinase pathway components in invasin-mediated internalization of Yersinia enterocolitica. Infect Immun. 2016;84:1826–41.PubMedCentralCrossRefPubMedGoogle Scholar
  9. Dubois T, Howell S, Zemlickova E, Aitken A. Identification of casein kinase I alpha interacting protein partners. FEBS Lett. 2002;517:167–71.CrossRefPubMedGoogle Scholar
  10. Dubois T, Zemlickova E, Howell S, Aitken A. Centaurin-alpha 1 associates in vitro and in vivo with nucleolin. Biochem Biophys Res Commun. 2003;301:502–8.CrossRefPubMedGoogle Scholar
  11. Galvita A, Grachev D, Azarashvili T, Baburina Y, Krestinina O, Stricker R, et al. The brain-specific protein, p42(IP4) (ADAP 1) is localized in mitochondria and involved in regulation of mitochondrial Ca2+. J Neurochem. 2009;109:1701–13.CrossRefPubMedGoogle Scholar
  12. Haase A, Nordmann C, Sedehizade F, Borrmann C, Reiser G. RanBPM a novel interaction partner of the brain-specific protein p42IP4/centaurin alpha-1. J Neurochem. 2008;105:2237–48.CrossRefPubMedGoogle Scholar
  13. Hammonds-Odie LP, Jackson TR, Profit AA, Blader IJ, Turck CW, Prestwich GD, et al. Identification and cloning of centaurin-alpha. A novel phosphatidylinositol 3,4,5-trisphosphate-binding protein from rat brain. J Biol Chem. 1996;271:18859–68.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Hanck T, Stricker R, Sedehizade F, Reiser G. Identification of gene structure and subcellular localization of human centaurin alpha 2, and p42IP4, a family of two highly homologous, Ins 1,3,4,5-P4−/PtdIns 3,4,5-P3-binding, adapter proteins. J Neurochem. 2004;88:326–36.CrossRefPubMedGoogle Scholar
  15. Hayashi H, Matsuzaki O, Muramatsu S, Tsuchiya Y, Harada T, Suzuki Y, et al. Centaurin-alpha1 is a phosphatidylinositol 3-kinase-dependent activator of ERK1/2 mitogen-activated protein kinases. J Biol Chem. 2006;281:1332–7.CrossRefPubMedGoogle Scholar
  16. Horiguchi K, Hanada T, Fukui Y, Chishti AH. Transport of PIP3 by GAKIN, a kinesin-3 family protein, regulates neuronal cell polarity. J Cell Biol. 2006;174:425–36.PubMedCentralCrossRefPubMedGoogle Scholar
  17. Kahn RA, Bruford E, Inoue H, Logsdon JM, Nie Z, Premont RT, et al. Consensus nomenclature for the human ArfGAP domain-containing proteins. J Cell Biol. 2008;182:1039–44.PubMedCentralCrossRefPubMedGoogle Scholar
  18. Kalscheuer VM, Musante L, Fang C, Hoffmann K, Fuchs C, Carta E, et al. A balanced chromosomal translocation disrupting ARHGEF9 is associated with epilepsy, anxiety, aggression, and mental retardation. Hum Mutat. 2009;30:61–8.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Kanamarlapudi V. Centaurin-alpha1 and KIF13B kinesin motor protein interaction in ARF6 signalling. Biochem Soc Trans. 2005;33:1279–81.CrossRefPubMedGoogle Scholar
  20. Kreutz MR, Böckers TM, Sabel BA, Hülser E, Stricker R, Reiser G. Expression and subcellular localization of p42IP4/centaurin-alpha, a brain-specific, high-affinity receptor for inositol 1,3,4,5-tetrakisphosphate and phosphatidylinositol 3,4,5-trisphosphate in rat brain. Eur J Neurosci. 1997a;9:2110–24.CrossRefPubMedGoogle Scholar
  21. Kreutz MR, Böckers TM, Sabel BA, Stricker R, Hülser E, Reiser G. Localization of a 42-kDa inositol 1,3,4,5-tetrakisphosphate receptor protein in retina and change in expression after optic nerve injury. Brain Res Mol Brain Res. 1997b;45:283–93.CrossRefPubMedGoogle Scholar
  22. Lawrence J, Mundell SJ, Yun H, Kelly E, Venkateswarlu K. Centaurin-alpha 1, an ADP-ribosylation factor 6 GTPase activating protein, inhibits beta 2-adrenoceptor internalization. Mol Pharmacol. 2005;67:1822–8.CrossRefPubMedGoogle Scholar
  23. Moore CD, Thacker EE, Larimore J, Gaston D, Underwood A, Kearns B, et al. The neuronal Arf GAP centaurin alpha1 modulates dendritic differentiation. J Cell Sci. 2007;120:2683–93.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Noseda R, Guerrero-Valero M, Alberizzi V, Previtali SC, Sherman DL, Palmisano M, et al. Kif13b regulates PNS and CNS myelination through the Dlg1 scaffold. PLoS Biol. 2016;14:e1002440.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Pellon-Cardenas O, Clancy J, Uwimpuhwe H, D’Souza-Schorey C. ARF6-regulated endocytosis of growth factor receptors links cadherin-based adhesion to canonical Wnt signaling in epithelia. Mol Cell Biol. 2013;33:2963–75.PubMedCentralCrossRefPubMedGoogle Scholar
  26. Rao VR, Corradetti MN, Chen J, Peng J, Yuan J, Prestwich GD, et al. Expression cloning of protein targets for 3-phosphorylated phosphoinositides. J Biol Chem. 1999;274:37893–900.CrossRefPubMedGoogle Scholar
  27. Reiser G, Bernstein HG. Neurons and plaques of Alzheimer’s disease patients highly express the neuronal membrane docking protein p42IP4/centaurin alpha. Neuroreport. 2002;13:2417–9.CrossRefPubMedGoogle Scholar
  28. Reiser G, Bernstein HG. Altered expression of protein p42IP4/centaurin-alpha 1 in Alzheimer’ disease brains and possible interaction of p42IP4 with nucleolin. Neuroreport. 2004;15:147–8.CrossRefPubMedGoogle Scholar
  29. Reiser G, Schafer R, Donie F, Hulser E, Nehls-Sahabandu M, Mayr GW. A high-affinity inositol 1,3,4,5-tetrakisphosphate receptor protein from brain is specifically labelled by a newly synthesized photoaffinity analogue, N-(4-azidosalicyl)aminoethanol(1)-1-phospho-D-myo-inositol 3,4,5-trisphosphate. Biochem J. 1991;280(Pt 2):533–9.Google Scholar
  30. Reiser G, Striggow F, Hackmann C, Schwegler H, Yilmazer-Hanke DM. Short-term down-regulation of the brain-specific, PtdIns(3,4,5)P3/Ins(1,3,4,5)P4-binding, adapter protein, p42IP4/centaurin-alpha 1 in rat brain after acoustic and electric stimulation. Neurochem Int. 2004;45:89–93.CrossRefPubMedGoogle Scholar
  31. Schweitzer JK, Sedgwick AE, D'Souza-Schorey C. ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis. Semin Cell Dev Biol. 2011;22:39–47.CrossRefPubMedGoogle Scholar
  32. Sedehizade F, Hanck T, Stricker R, Horstmayer A, Bernstein HG, Reiser G. Cellular expression and subcellular localization of the human Ins(1,3,4,5)P(4)-binding protein, p42(IP4), in human brain and in neuronal cells. Brain Res Mol Brain Res. 2002;99:1–11.CrossRefPubMedGoogle Scholar
  33. Sedehizade F, von Klot C, Hanck T, Reiser G. p42(IP4)/centaurin alpha1, a brain-specific PtdIns(3,4,5)P3/Ins(1,3,4,5)P4-binding protein: membrane trafficking induced by epidermal growth factor is inhibited by stimulation of phospholipase C-coupled thrombin receptor. Neurochem Res. 2005;30:1319–30.CrossRefPubMedGoogle Scholar
  34. Stricker R, Chang YT, Chung SK, Reiser G. Determination of specificity of a high-affinity inositol 1,3,4,5-tetrakisphosphate binding site at a 42 kDa receptor protein, p42IP4: comparison of affinities of all inositoltris-,-tetrakis-, and -pentakisphosphate regioisomers. Biochem Biophys Res Commun. 1996;228:596–604.CrossRefPubMedGoogle Scholar
  35. Stricker R, Hülser E, Fischer J, Jarchau T, Walter U, Lottspeich F, et al. cDNA cloning of porcine p42IP4, a membrane-associated and cytosolic 42 kDa inositol(1,3,4,5)tetrakisphosphate receptor from pig brain with similarly high affinity for phosphatidylinositol (3,4,5)P3. FEBS Lett. 1997;405:229–36.CrossRefPubMedGoogle Scholar
  36. Stricker R, Vandekerckhove J, Krishna MU, Falck JR, Hanck T, Reiser G. Oligomerization controls in tissue-specific manner ligand binding of native, affinity-purified p42(IP4)/centaurin alpha1 and cytohesins-proteins with high affinity for the messengers d-inositol 1,3,4,5-tetrakisphosphate/phosphatidylinositol 3,4,5-trisphosphate. Biochim Biophys Acta. 2003;1651:102–15.CrossRefPubMedGoogle Scholar
  37. Stricker R, Chow KM, Walther D, Hanck T, Hersh LB, Reiser G. Interaction of the brain-specific protein p42IP4/centaurin-alpha1 with the peptidase nardilysin is regulated by the cognate ligands of p42IP4, PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4, with stereospecificity. J Neurochem. 2006;98:343–54.CrossRefPubMedGoogle Scholar
  38. Szatmari EM, Oliverisa AF, Sumner EJ, Yasuda R. Centaurin- 1-Ras-Elk-1 signaling at mitochondria mediates amyloid-induced synaptic dysfunction. J Neurosci. 2013;33:5367–74.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Tanaka K, Horiguchi K, Yoshida T, Takeda M, Fujisawa H, Takeuchi K, et al. Evidence that a phosphatidylinositol 3,4,5-trisphosphate-binding protein can function in nucleus. J Biol Chem. 1999;274:3919–22.CrossRefPubMedGoogle Scholar
  40. Thacker EE, Kearns B, Chapman C, Hammond J, Howell A, Theibert AB. The arf6 GAP centaurin alpha-1 is a neuronal actin-binding protein which also functions via GAP-independent activity to regulate the actin cytoskeleton. Eur J Cell Biol. 2004;83:541–54.CrossRefPubMedGoogle Scholar
  41. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem. 2001;70:535–602.CrossRefPubMedGoogle Scholar
  42. Venkateswarlu K, Cullen PJ. Molecular cloning and functional characterization of a human homologue of centaurin-alpha. Biochem Biophys Res Commun. 1999;262:237–44.CrossRefPubMedGoogle Scholar
  43. Venkateswarlu K, Oatey PB, Tavaré JM, Jackson TR, Cullen PJ. Identification of centaurin-alpha1 as a potential in vivo phosphatidylinositol 3,4,5-trisphosphate-binding protein that is functionally homologous to the yeast ADP-ribosylation factor (ARF) GTPase-activating protein, Gcs1. Biochem J. 1999;340:359–63.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Venkateswarlu K, Brandom KG, Lawrence JL. Centaurin-alpha1 is an in vivo phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating protein for ARF6 that is involved in actin cytoskeleton organization. J Biol Chem. 2004;279:6205–8.CrossRefPubMedGoogle Scholar
  45. Venkateswarlu K, Hanada T, Chishti AH. Centaurin-alpha1 interacts directly with kinesin motor protein KIF13B. J Cell Sci. 2005;118:2471–84.CrossRefPubMedGoogle Scholar
  46. Whitley P, Gibbard AM, Koumanov F, Oldfield S, Kilgour EE, Prestwich GD, et al. Identification of centaurin-alpha2: a phosphatidylinositide-binding protein present in fat, heart and skeletal muscle. Eur J Cell Biol. 2002;81:222–30.CrossRefPubMedGoogle Scholar
  47. Zemlickova E, Dubois T, Kerai P, Clokie S, Cronshaw AD, Wakefield RI, et al. Centaurin-alpha(1) associates with and is phosphorylated by isoforms of protein kinase C. Biochem Biophys Res Commun. 2003;307:459–65.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Benjamin J. Gosney
    • 1
  • Christian R. Robinson
    • 1
    • 2
  • Venkateswarlu Kanamarlapudi
    • 1
  1. 1.Institute of Life Science 1, School of MedicineSwansea UniversitySwanseaUK
  2. 2.Calon Cardio-Technology Ltd, Institute of Life Science 2Medical School, Swansea UniversitySwanseaUK