Ras-Associating Domain Proteins: A New Class of Cyclic Nucleotide-Gated Channel Modulators

  • Vivek K. Gupta
  • Ammaji Rajala
  • Raju V. S. RajalaEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)


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.


Cyclic nucleotide-gated channel Ras-associating domain Growth factor receptor bound protein-14 Photoreceptor PHLPP1 PHLPP2 



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.


  1. 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
  2. Corpet, F (1988) Multiple sequence alignment with hierarchical clustering. Nucl. Acids Res. 16: 10881–10890PubMedCrossRefGoogle Scholar
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Kaupp UB and Seifert R (2002) Cyclic nucleotide-gated ion channels. Physiol Rev 82:769–824PubMedGoogle Scholar
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. Raaijmakers JH, Bos JL (2009) Specificity in Ras and rap signaling. J Biol Chem 284: 10995–10999PubMedCrossRefGoogle Scholar
  20. Tanaka M, Ohashi R, Nakamura R et al (2004) Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2. EMBO J 10:1075–1088CrossRefGoogle Scholar
  21. Yau KW, Hardie RC (2009) Phototransduction motifs and variations. Cell 139:246–64PubMedCrossRefGoogle Scholar
  22. Yau KW, Baylor DA (1989) Cyclic GMP-activated conductance of retinal photoreceptor cells. Annu Rev Neurosci 12:289–327PubMedCrossRefGoogle Scholar
  23. Wigler M, Pellicer A, Silverstein S, Axel R (1978) Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor. Cell 14:725–731PubMedCrossRefGoogle Scholar
  24. Wissinger B, Gamer D, Jagle H et al (2001) CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet 69:722–37PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Vivek K. Gupta
    • 1
  • Ammaji Rajala
    • 1
  • Raju V. S. Rajala
    • 2
    Email author
  1. 1.Department of Ophthalmology, Dean A. McGee Eye InstituteUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Departments of Ophthalmology and Cell Biology, Dean A. McGee Eye InstituteUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations