The Ras is a protein subfamily of small GTPases that are involved in cellular signal transduction. Members of Ras family are all related in structure and regulate diverse cell behaviors. Ras-associating/binding (RA/RBD) domain-containing proteins perform several different functions ranging from tumor suppression to being oncoproteins. Their role in different biological processes may be unclear and highly divergent but what is clear is that they convergently function by interacting with Ras proteins through their RA/RBD subdomains directly or indirectly. Apart from interacting with Ras proteins, there is no perceptible relationship between these proteins or their highly unrelated protein bodies. The heterogeneity among these RA domains allows them to interact with Ras proteins of different types as well as several other proteins which contain similar motifs. Very recently, we have demonstrated that growth factor receptor bound protein 14 (Grb14) RA domain binds to photoreceptor cyclic nucleotide-gated channel (CNG) and inhibits its activity in vivo. In this study, we have examined two other RA domain-containing protein phosphates expressed in retina, PHLPP1, and PHLPP2 on CNG channel activity. Our data indicate that not all RA domain proteins are modulators of CNG channel, suggesting the existence of heterogeneity among several RA domain proteins.
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This work was supported by grants from the NIH (EY016507; EY00871; EY12190). Vivek K. Gupta received a travel award to attend the XIVth International Symposium on Retinal Degeneration held at Mont-Tremblant, Quebec, Canada, 2010.
Biel M, Zong X, Ludwig A et al (1999) Structure and function of cyclic nucleotide-gated channels. Rev Physiol Biochem Pharmacol 135:151–71PubMedCrossRefGoogle Scholar
Dryja TP, Finn JT, Peng YW et al (1995) Mutations in the gene encoding the alpha subunit of the rod cGMP-gated channel in autosomal recessive retinitis pigmentosa. Proc. Natl. Acad. Sci. USA. 92:10177–10181PubMedCrossRefGoogle Scholar
Gao T, Furnari F, Newton AC (2005) PHLPP: A Phosphatase that Directly Dephosphorylates Akt, Promotes Apoptosis, and Suppresses Tumor Growth. Mol Cell 18:13–24PubMedCrossRefGoogle Scholar
Gao MH, Miyanohara A, Feramisco JR et al (2009) Activation of PH-domain Leucine-Rich Protein Phosphatase 2 (PHLPP2) by Agonist Stimulation in Cardiac Myocytes Expressing Adenyl Cyclase Type 6. Biochem Biophys Res Commun 26:193–198CrossRefGoogle Scholar
Gerstner A, Zong X, Hofmann F et al (2000) Molecular cloning and functional characterization of a new modulatory cyclic nucleotide-gated channel subunit from mouse retina. J Neurosci 20:1324–32PubMedGoogle Scholar
Gupta VK, Rajala A, Daly RJ et al (2010) Growth factor receptor-bound protein 14: a new modulator of photoreceptor-specific cyclic-nucleotide-gated channel. EMBO Rep. 11:861–867PubMedCrossRefGoogle Scholar
Ivins JK, Parry MK, Long DA (2004) A Novel cAMP-Dependent Pathway Activates Neuronal integrin Function in Retinal Neurons. The Journal of Neuroscience 24:1212–1216PubMedCrossRefGoogle Scholar
Kaupp UB and Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824PubMedGoogle Scholar
Kanai-Azuma M, Mattick JS, Kaibuchi K et al (2000) Co-localization of FAM and AF-6, the mammalian homologues of Drosophila faf and canoe, in mouse eye development. Mechanisms of Development 91:2383–386CrossRefGoogle Scholar
Kanan Y, Matsumoto H, Song H et al (2010) Serine/threonine kinase akt activation regulates the activity of retinal serine/threonine phosphatases, PHLPP and PHLPPL. J Neurochem 113:477–488PubMedCrossRefGoogle Scholar
Kohl S, Baumann B, Broghammer M et al (2000) Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 9:2107–16PubMedCrossRefGoogle Scholar
Kohl S, Varsanyi B, Antunes GA et al (2005) CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet 13:302–8PubMedCrossRefGoogle Scholar
Nishiguchi KM, Sandberg MA, Gorji N et al (2005) Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat 25:248–58PubMedCrossRefGoogle Scholar
Pimentel B, Sanz C, Varela-Nieto I et al (2000) c-Raf regulates cell survival and retinal ganglion cell morphogenesis during neurogenesis. J Neurosci 20:3254–3262PubMedGoogle Scholar
Rajala RVS, McClellan ME, Ash JD et al (2002) In Vivo Regulation of Phosphoinositide 3-Kinase in Retina through Light-induced Tyrosine Phosphorylation of the Insulin Receptor β-Subunit. J Biol Chem 277:43319–43326PubMedCrossRefGoogle Scholar
Rajala RVS, Chan MD, Rajala A (2005) Lipid − Protein Interactions of Growth Factor Receptor-Bound Protein 14 in Insulin Receptor Signaling. Biochemistry 44:15461–15471PubMedCrossRefGoogle Scholar
Rajala A, Daly RJ, Tanito M et al (2009) Growth factor receptor-bound protein 14 undergoes light-dependent intracellular translocation in rod photoreceptors: functional role in retinal insulin receptor activation. Biochemistry 48:5563–72PubMedCrossRefGoogle Scholar