Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Slp (Synaptotagmin-Like Protein)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_560

Synonyms

Historical Background

Synaptotagmin-like proteins (Slps) were originally identified as synaptotagmin-related molecules containing two C2 calcium/phospholipid-binding motifs (named the C2A domain and the C2B domain) at their C terminus and no transmembrane domain at their N terminus (Fig. 1a), which suggested that they regulate certain intracellular membrane traffic events, the same as synaptotagmin I (Syt I) does in synaptic vesicle traffic (Fukuda and Mikoshiba 2001). The Slp family of proteins is now defined as a family of proteins, each of which contains an N-terminal conserved motif named the Slp homology domain (SHD) (Fig. 1a, magenta boxes) and C-terminal tandem C2 domains, although some members of the Slp family have several isoforms (e.g., Slp2-b, Slp3-b, and Slp4-b) that lack one of these domains because of alternative splicing (Fig. 1a, bars and arrows) (Fukuda et al. 2001). The Slp family is also recognized as the third group of C-terminal-type tandem C2 proteins that form a branch distinct from the synaptotagmin family and the rabphilin/Doc2 family in the phylogenetic tree (Fig. 1b). Slp family members appear to be conserved in all vertebrates, and five members of the Slp family (Slp1-5) have been reported in humans and mice (Wang et al. 1999; Fukuda and Mikoshiba 2001; McAdara Berkowitz et al. 2001; Kuroda et al. 2002b). One Slp homologue (named bitesiz; Btsz) was found in Drosophila, but it lacks the characteristic SHD at the N terminus. Since mouse Slp mRNAs are differentially distributed in different tissues and at different developmental stages, Slp family members have been suggested to play a tissue-specific or cell-type-specific role in membrane traffic.
Slp (Synaptotagmin-Like Protein), Fig. 1

Structure of Slp family members. (a) Comparison of Slp family members with Syt I and rabphilin. Syt I, the Slp family members, and rabphilin share the tandem C2 domains (i.e., the C2A domain and the C2B domain; blue boxes) at their C terminus, but their N-terminal structures differ. Syt I contains a single transmembrane domain (TM, black box), whereas the Slp family members contain a unique Slp homology domain (SHD, magenta boxes), also known as RBD27 (Rab-binding domain specific for Rab27 isoforms) (Fukuda et al. 2001; Kuroda et al. 2002a). The SHD of Slp3-5 is divided by zinc finger motifs (Zn2+). Short bars (2 S-I, 2 S-II, 2 S-III, 5 S-I) and arrows (Slp2-b, Slp3-b, and Slp4-b) indicate the positions of alternative splicing sites. Amino acid numbers are given on both sides. (b) Molecular dendrogram of the mouse C-terminal-type tandem C2 proteins, including members of the synaptotagmin family ( blue branch), the Slp family ( red branch), and the rabphilin/Doc2 family (green branch). The dendrogram was drawn by using the ClustalW program set at the default parameters (available at http://clustalw.ddbj.nig.ac.jp)

The common function of Slp family proteins was first revealed by biochemical analysis of the SHD, which has relatively weak amino acid sequence similarity to the Rab-binding domain of rabphilin, another type of C-terminal-type tandem C2 protein (Fig. 1a, bottom) (Fukuda et al. 2001). The results of an investigation of the ability of the SHD to bind all Rab isoforms clearly indicated that it serves as a specific effector domain for Rab27A and Rab27B (Kuroda et al. 2002a). The Rab27-binding SHD is also found in the N-terminal domain of another protein family, the Slac2 (Slp homologue lacking C2 domains) family, which consists of Slac2-a/melanophilin, Slac2-b, and Slac2-c/MyRIP (Fukuda 2013). The structures of the SHD complexed with Rab27 have already been determined (Fukuda 2013). Rab27 belongs to the Rab-type small GTPase family and functions as a molecular switch by cycling between two nucleotide-bound states, a GTP-bound active state, and a GDP-bound inactive state. The GTP-bound form of Rab27 is recruited to specific membrane compartments, e.g., to melanosomes in melanocytes and to secretory vesicles in secretory and nonsecretory cells, and interacts with its specific effector, namely, one of the members of the Slp family (Fukuda 2013). The Rab27 effector function of the Slp family members in melanosome transport and secretory granule exocytosis has been revealed during the past few decades, and the proposed function of each Slp is described below.

Slp1/JFC1

Slp1 was independently identified as JFC1, an NADPH oxidase- and phosphatidylinositol 3,4,5-trisphosphate (PIP3)-binding protein (McAdara Berkowitz et al. 2001). In contrast to other SHDs, the SHD of Slp1 and Slp2-a lacks zinc finger motifs (Fig. 1a), but it still specifically recognizes Rab27 isoforms (Kuroda et al. 2002a). Mouse Slp1 protein is most abundantly expressed in the pancreas, especially in pancreatic acinar cells, and it is also expressed in other cell types, including neutrophils (Brzezinska et al. 2008), neurons (Arimura et al. 2009), platelets (Neumüller et al. 2009), human prostate carcinoma cells, and cytotoxic T lymphocytes (Holt et al. 2008). In neutrophils, Slp1 is colocalized with Rab27A on myeloperoxidase (MPO)-containing azurophilic granules, and knockdown of Slp1 by short hairpin RNA has been found to impair MPO secretion (Brzezinska et al. 2008). The Rab27A·Slp1 complex has been proposed to regulate the tethering and/or docking step of azurophilic granule exocytosis, possibly through interaction with PIP 3 in the plasma membrane. Slp1 also promotes actin remodeling during azurophilic granule exocytosis through its interaction with RhoA-GTPase-activating protein (GAP) Gem-interacting protein (GMIP). Similarly, Slp1 has been suggested to control other secretion events, including prostate-specific antigen secretion by human prostate carcinoma cells, dense granule exocytosis by platelets, and lytic granule exocytosis by cytotoxic T lymphocytes. Notably, Slp1 has also been found to form a complex with Rab27B·CRMP-2·TrkB·kinesin-1 and to mediate anterograde transport in axons (Arimura et al. 2009). Involvement of Slp1 in Rab8-dependent membrane traffic events has been reported, but whether Rab8 binds to Slp1 is a matter of controversy in the literature.

Despite the important roles of Slp1 at the cellular level, Slp1 knockout (KO) mice are viable, and no obvious abnormalities have been detected in their neurons or immune cells (Holt et al. 2008). The Slp1-deficiency in Slp1 KO mice may be compensated by a Slp1-related protein, Slp2-a. Slight differences in the pancreatic acinar cells, pancreatic β cells, and neutrophils of wild-type mice and Slp1 KO mice have been reported, e.g., the pancreatic acinar cells of fasted Slp1 KO mice have been reported to contain a higher number of zymogen granules.

Slp2

Slp2-a is the largest member of the Slp family. A variety of Slp2 isoforms that have resulted from tissue-/cell-type-specific alternative splicing events have been reported in the literature (Fukuda et al. 2001; Holt et al. 2008) (Fig. 1a), but the physiological significance of the presence of multiple Slp2 isoforms remains unknown. The Slp2-a isoform contains an N-terminal SHD, whereas the Slp2-b and Slp2-c isoforms lack this domain. Mouse Slp2-a protein is most abundantly expressed in the stomach, especially in gastric surface mucous cells (Saegusa et al. 2006), and it is also expressed in other cell types, including melanocytes (Kuroda and Fukuda 2004), pancreatic α cells, and cytotoxic T lymphocytes (Holt et al. 2008). The well-known function of Slp2-a is to anchor melanosomes to the plasma membrane by simultaneously interacting with Rab27A on the melanosome via its SHD and with phosphatidylserine (PS) in the plasma membrane via its C2A domain (Kuroda and Fukuda 2004). Slp2-a also regulates the elongated cell shape of melanocytes by an unknown mechanism that is independent of Rab27A (Kuroda and Fukuda 2004). Slp2-a is also involved in the docking of mucus granules to the apical plasma membrane of the gastric surface mucous cells, because a smaller number of mucus granules and docking defect have been observed in the gastric surface mucous cells of Slp2-a KO mice (Saegusa et al. 2006). An inhibitory role of Slp2-a in glucagon secretion has been proposed based on the results of an overexpression study, but the function of endogenous Slp2-a in pancreatic α cells is currently unknown.

Involvement of Slp2-a in polarized trafficking in renal epithelial cells, especially in the docking of podocalyxin-containing vesicles with the apical membrane, has recently been reported (Gálvez-Santisteban et al. 2012). Knockdown of Slp2-a in Madin-Darby canine kidney (MDCK) II cells has been shown to cause reduced expression of the tight junction protein claudin-2 in two-dimensional monolayers and to impair single lumen formation in three-dimensional cysts. Interestingly, Slp2-a also regulates renal epithelial cell size through its interaction with Rap1GAPs and protein phosphatase 1β (PP1β) (Yasuda and Fukuda 2014).

Three possible links between human disease and Slp2-a have been reported. The first link is based on the fact that the Slp2-a protein level is dramatically reduced in the cytotoxic T lymphocytes of type II Griscelli syndrome (GS) patients (i.e., Rab27A-deficient) (Holt et al. 2008). Its reduction is presumably attributable to proteolysis, because Slp2-a contains multiple PEST sequences, which are potential signals for rapid protein degradation (Holt et al. 2008). In addition, the I44T mutation of Rab27A in type II GS results in reduced binding activity to Slp2-a. However, cytotoxic T lymphocytes from Slp2-a KO mice exhibit normal killing activity (i.e., normal lytic granule exocytosis), suggesting that the Slp2-a-deficiency may be compensated by a Slp2-a-related protein, Slp1. The second link is based on the fact that dysferlin-deficiency has been shown to cause compensatory induction of Slp2-a (and also Rab27A) in limb girdle muscular dystrophy 2B (LGMD2B) muscles, and its induction may contribute to the onset of inflammation in patient muscles. The third link is based on the fact that Rab27A and Slp2-a control human immunodeficiency virus-1 (HIV-1) assembly in Jurkat cells.

Slp3

Although Slp3 mRNA is expressed in mouse spleen, lung, kidney, and testis (Fukuda et al. 2001), almost nothing is known about the protein expression of Slp3. Two alternative splicing isoforms, Slp3-a and Slp3-b (Fig. 1a), have been reported, and the former form contains an N-terminal SHD with zinc finger domains. The results of an in vitro binding study indicated that the C2A domain of Slp3 and Slp5 functions as an atypical Ca2+-dependent phospholipid-binding domain (Fukuda 2002), although key Glu/Asp residues responsible for Ca2+ binding of the C2 domain of Syt I and protein kinase C (PKC) are missing in the C2A domain of Slp3 and Slp5. Interestingly, expression of these Ca2+-dependent-type Slps (i.e., Slp3-a and Slp5) in neuroendocrine PC12 cells strongly induced hormone secretion without changing the number of hormone granules docked at the plasma membrane (Tsuboi and Fukuda 2006). By contrast, Ca2+-independent-type Slps (i.e., Slp1, Slp2-a, and Slp4-a) had no effect or else had an inhibitory effect on hormone secretion by PC12 cells. In addition to controlling secretory vesicle exocytosis, Slp3-a has been shown to form a complex with Rab27A·kinesin-1 and to mediate transport of lytic granules to the immunological synapse, and involvement of Slp3-a in HIV-1 assembly has recently been reported.

Slp4/Granuphilin

Slp4/granuphilin was originally identified as a rabphilin-like protein associated with insulin granules in pancreatic β cells (Wang et al. 1999). Two alternative splicing isoforms, Slp4-a/granuphilin-a and Slp4-b/granuphilin-b, have been reported, and both of them contain an N-terminal SHD (Fig. 1a). However, no differences in the function of the two isoforms are unknown. Mouse Slp4-a protein is most abundantly expressed in the pancreas, especially in pancreatic β cells (Wang et al. 1999), and it is also expressed in other neuroendocrine cells (Tsuboi and Fukuda 2006), parotid acinar cells, endothelial cells, HeLa cells (Ostrowski et al. 2010), osteoblasts, and renal epithelial cells (Gálvez-Santisteban et al. 2012). In contrast to other Slp family members, Slp4-a functions as a negative regulator of hormone secretion by neuroendocrine cells, including pancreatic β cells and PC12 cells (Wang et al. 1999), although expression of Slp4-a promotes docking of hormone granules to the plasma membrane, possibly through interaction with Munc18-1·syntaxin-1a complex (Gomi et al. 2005; Tsuboi and Fukuda 2006; Tomas et al. 2008). Small interfering RNA-mediated knockdown of endogenous Slp4-a or targeted disruption of the Slp4-a gene has been found to actually cause increased hormone secretion despite decreasing the number of plasma membrane-docked hormone granules (Gomi et al. 2005; Tsuboi and Fukuda 2006), indicating that exocytosis occurs mainly from undocked hormone granules. Therefore, Slp4-a may be a potential therapeutic target for the treatment of type 2 diabetes.

In contrast to the negative role of Slp4-a in hormone secretion, positive roles of Slp4-a have been reported in other cell types. For example, Slp4-a is present on amylase-containing granules in parotid acinar cells together with Rab27A/B and forms a complex with Munc18-2·syntaxin-2/3. Disruption of the Slp4-a·Munc18-2·syntaxin-2/3 complex either by a GST-Slp4-a linker, which contains a Munc18-2-binding region, or antibody against the Slp4-a linker domain attenuates isoproterenol-stimulated amylase release from streptolysin O-permeabilized parotid acinar cells. Slp4-a is also expressed in HeLa cells and contributes to exososme secretion through interaction with Rab27A (Ostrowski et al. 2010). Moreover, Slp4-a has been shown to be involved in polarized trafficking in renal epithelial cells, especially in the tethering and fusion of podocalyxin-containing vesicles with the apical membrane (Gálvez-Santisteban et al. 2012).

Slp5

Slp5 was identified as a protein closely related to Slp4-a, and the genes encoding both are located on the same X chromosome in humans, rats, and mice (Kuroda et al. 2002b). However, the biochemical properties of Slp4-a and Slp5 are clearly different in terms of Ca2+-dependent phospholipid-binding activity and Munc18-1·syntaxin-1a–binding activity (Wang et al. 1999; Kuroda et al. 2002b; Tsuboi and Fukuda 2006). Abundant expression of human Slp5 mRNA has been found in the placenta and liver, but its precise protein expression patterns remain to be determined. Although expression of Slp5 protein has been reported in some pancreatic β cell lines, its involvement in insulin secretion has never been investigated. As noted above in the section on Slp3, however, expression of Slp5 in neuroendocrine PC12 cells strongly induces hormone secretion without changing the number of hormone granules docked at the plasma membrane (Tsuboi and Fukuda 2006). Involvement of Slp5 in RANKL release by osteoblasts and in cell migration by lymphocytes has also been reported, but the precise mechanisms of its involvement are poorly understood.

Summary

The members of the Slp family of proteins are well-known Rab27 effectors that function in specific membrane traffic events (reviewed in Fukuda 2013) (summarized in Table 1). Although each member participates in a different type of membrane traffic event, we found a common molecular mechanism that underlies the Slp-mediated membrane traffic (Fig. 2). Since Slp family proteins are first recruited to the specific vesicle/organelle where the GTP-bound active form of Rab27 is present, and their C-terminal domain interacts with their specific receptor protein (R in Fig. 2) in the plasma membrane, members of the Slp family of proteins function as linkers between cargo (i.e., Rab27-containing vesicle/organelle) and target membrane and promote tethering/docking/fusion of the Rab27-containing vesicle/organelle to the target membrane. Moreover, Slp1 and Slp3-a interact with motor molecules via the effector molecules and mediate the transport of Rab27-containing vesicles/organelles (Fukuda 2013). Future determination of the detailed expression pattern of each Slp member and identification of more tissue-/cell-type-specific binding partners of Slps, especially Slp3-a and Slp5, will be necessary to fully understand the molecular mechanism of Slp-mediated membrane traffic.
Slp (Synaptotagmin-Like Protein), Table 1

Proposed functions and distribution of Slp family members

Name (gene ID)

Binding partners (binding site)

Proposed functions, distribution, and other features

KO mouse phenotypes

Slp1/JFC1

(mouse: 269,589)

(human: 84,958)

CRMP-2 (N terminus)

Rab27 (SHD)

Rab8

EPI64 (SHD)

PIP 3 (C2A)

TrkB (C2A)

Rap1GAP2 (C2A)

RhoA-GAP GMIP

NADPH oxidase

Control of prostate-specific antigen secretion by human prostate carcinoma cells

Control of azurophilic granule exocytosis by neutrophils

Control of TrkB transport in axons

Control of dense granule secretion by platelets

Control of amylase secretion by pancreatic acinar cells

Control of insulin secretion by pancreatic β cells

Possible involvement of lytic granule exocytosis by cytotoxic T lymphocytes

Phosphorylation of Slp1 at serine 241 by Akt

Viable

No apparent abnormalities in general appearance or behavior

Increased zymogen granules in pancreatic acinar cells of the fasted Slp1 KO mice

Increased RhoA activity in neutrophils of Slp1 KO mice

Decreased high-KCl-dependent insulin secretion from undocked vesicles

Slp2

(mouse: 83,671)

(human: 54,843)

Rab27 (SHD)

PS (C2A)

PIP 2 (C2A)

RAP1GAPs (C2B)

PP1β (linker domain)

Melanosome anchoring to the plasma membrane

Control of basal mucus secretion by gastric surface mucous cells

Control of glucagon secretion by pancreatic α cells

Docking of podocalyxin-containing vesicles with the apical membrane in renal epithelial cells

Control of renal epithelial cell size

Compensatory induction of Slp2-a in limb girdle muscular dystrophy 2B (LGMD2B) muscles

Deficiency of Slp2-a protein in cytotoxic T lymphocytes from type II Griscelli syndrome patients

Control of HIV-1 assembly

Viable

No apparent abnormalities in general appearance or behavior

Decreased basal mucus secretion by gastric surface mucous cells of Slp2-a KO mice

Slp3

(mouse: 83,672)

(human: 94,120)

Rab27 (SHD)

PS (C2A) a

KLC1 (linker domain)

Enhancement of hormone secretion by PC12 cells, when Slp3-a is overexpressed

Control of lytic granule transport by cytotoxic T lymphocytes

Control of HIV-1 assembly

None produced yet

Slp4/granuphilin

(mouse: 27,359)

(human: 94,121)

Rab3/8/27 (SHD)

Munc18-1·syntaxin-1a (linker domain)

Munc18-2·syntaxin-2/3 (linker domain)

Control of insulin secretion by pancreatic β cells

Control of dense-core vesicle exocytosis by PC12 cells

Control of amylase secretion by parotid acinar cells

Control of pituitary hormone secretion by pituitary cells

Control of von Willebrand factor (VWF) secretion by endothelial cells

Control of dense granule secretion by platelets

Control of RANKL release by osteoblasts

Control of exosome secretion by HeLa cells

Tethering/fusion of podocalyxin-containing vesicles with the apical membrane in renal epithelial cells

Viable

No apparent abnormalities in general appearance or behavior

Very mild growth defect (10% weight reduction)

Increased insulin secretion

Slp5

(mouse: 236,643)

(human: 94,122)

Rab27 (SHD)

PS (C2A/C2B)a

Enhancement of hormone secretion by PC12 cells, when Slp5 is overexpressed

Expression of Slp5 protein in pancreatic β cell lines

Control of RANKL release by osteoblasts

Control of lymphocyte migration

None produced yet

aThe C2A domain of Slp3 and Slp5 exhibits Ca2+-dependent phospholipid-binding activity.

Slp (Synaptotagmin-Like Protein), Fig. 2

Proposed function of Rab27·Slp complex in the transport of a Rab27-bearing vesicle/organelle. The Slp is recruited to a certain vesicle/organelle by direct binding of the SHD to GTP-Rab27 via an active GTP-Rab27 specifically localized there. The Slp also interacts with a certain receptor (R) in the plasma membrane, and the resulting Rab27·Slp complex mediates tethering, docking, and/or fusion of the transport vesicle/organelle. Thus, Slp family members function as a linker protein between Rab27 on a vesicle/organelle and protein/lipid in the plasma membrane (Fukuda 2013). Examples of “R” are syntaxin-1a/Munc18-1 for Slp4-a/granuphilin-a (Gomi et al. 2005; Tsuboi and Fukuda 2006; Tomas et al. 2008), PS and PIP2 for Slp2-a (Kuroda and Fukuda 2004; Gálvez-Santisteban et al. 2012), and PIP 3 for Slp1/JFC1

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and NeurosciencesGraduate School of Life Sciences, Tohoku UniversitySendaiJapan