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Gene Review

GIT1  -  G protein-coupled receptor kinase...

Homo sapiens

Synonyms: ARF GAP GIT1, ARF GTPase-activating protein GIT1, CAT-1, CAT1, Cool-associated and tyrosine-phosphorylated protein 1, ...
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Disease relevance of GIT1

  • We have found that the response of Cat1 to osmotic stress and dehydration is not via an ABA-mediated pathway in young leaves, suggesting that there are two different mechanisms by which Cat1 responds to osmotic stress in embryos and in leaves [1].
  • In 10 patients with cat asthma and hay fever, we quantified the doses of cat allergen (expressed as cat allergen 1 [Cat-1] in log Food and Drug Administration [FDA] units) inspired from the ambient air of a room containing living cats required to induce a 20% drop in FEV1 [2].

Psychiatry related information on GIT1

  • A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease [3].
  • These results demonstrate a novel function for GIT1 as a key regulator of spine morphology and synapse formation and point to a potential mechanism by which mutations in Rho family signaling leads to decreased neuronal connectivity and cognitive defects in nonsyndromic mental retardation [4].

High impact information on GIT1

  • Active PAK1 is particularly evident in mitosis and phosphorylates the centrosomal adaptor GIT1 on serine 517 [5].
  • However, it is not clear whether GITs function to activate or repress motility or if the predominant GIT forms, GIT1 and GIT2, serve distinct or redundant roles [6].
  • In addition, ARF6, a major target for GIT1, is activated during TSH stimulation of HEK293 and FRTL-5 thyroid cells, and plays a key role in TSHR recycling [7].
  • We used dominant-negative constructs and small interfering RNA to show that TSHR recycling is regulated by the interaction between hScrib and betaPIX, and by the activity of GIT1 [7].
  • The phenotype results from mislocalized GIT1 and its binding partner PIX, an exchange factor for Rac [4].

Biological context of GIT1

  • Overexpression of GIT1 in fibroblasts or epithelial cells causes a loss of paxillin from FCs and stimulates cell motility [8].
  • Although GIT2 shares many properties with GIT1, it also exhibits both structural and functional diversity due to tissue-specific alternative splicing [9].
  • Point mutations in the SHD of GIT1 differentially interfere with the association of GIT1 with Piccolo, betaPIX, and focal adhesion kinase, suggesting that these proteins bind to the SHD by different mechanisms [10].
  • Depletion of GIT1 with antisense GIT1 oligonucleotides had no effect on basal cell morphology, but increased cell rounding and contraction of HUVECs, increased FA formation, and increased FAK tyrosine phosphorylation in response to thrombin, concomitant with increased endothelial hyperpermeability [11].
  • These data identify GIT1 as a novel mediator in agonist-dependent signaling in ECs, demonstrate that GIT1 is involved in cell shape changes, and suggest a role for GIT1 as a negative feedback regulator that augments recovery of cell contraction [11].

Anatomical context of GIT1


Associations of GIT1 with chemical compounds

  • GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor [16].
  • Phosphorylation of serine 709 in GIT1 regulates protrusive activity in cells [17].
  • KIF1A cofractionates and coimmunopreciptates with liprin-alpha and various liprin-alpha-associated membrane, signaling, and scaffolding proteins including alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptors, GRIP/ABP, RIM, GIT1, and beta PIX [18].
  • We also found that the VP1 trans-acting factor is not required for the induction of Cat1 by ABA in leaves, but may play a role in stabilizing the Cat1 transcript after an initial induction [1].
  • A permease encoded by the GIT1 gene imports extracellular glycerophosphodiesters across the plasma membrane, where their hydrolytic products can provide crucial nutrients such as inositol, choline, and phosphate to the cell [19].

Physical interactions of GIT1


Enzymatic interactions of GIT1


Regulatory relationships of GIT1

  • Regulation of neuroendocrine exocytosis by the ARF6 GTPase-activating protein GIT1 [23].
  • Furthermore, GIT1 targets constitutively activated PAK to adhesions and the leading edge via its interaction with paxillin [24].

Other interactions of GIT1

  • The longest form of GIT2 is colinear with GIT1 and shares the same domain structure, whereas one major splice variant prominent in immune tissues completely lacks the carboxyl-terminal domain [9].
  • This is due to the direct interaction of a C-terminal 125-residue domain of GIT1 with paxillin, under the regulation of PIX [8].
  • We propose that GIT1 and FAK cooperate to promote motility both by directly regulating focal complex dynamics and by the activation of Rac [8].
  • Overexpression of GIT1 leads to reduced beta2-adrenergic receptor signaling and increased receptor phosphorylation, which result from reduced receptor internalization and resensitization [13].
  • Based on this binding motif, we identify potential new binding partners of Nck1 and Nck2 and confirm this experimentally for the Arf-GAP GIT1 [25].

Analytical, diagnostic and therapeutic context of GIT1


  1. Catalase transcript accumulation in response to dehydration and osmotic stress in leaves of maize viviparous mutants. Guan, L.M., Scandalios, J.G. Redox Rep. (2000) [Pubmed]
  2. Dose of cat (Felis domesticus) allergen 1 (Fel d 1) that induces asthma. Van Metre, T.E., Marsh, D.G., Adkinson, N.F., Fish, J.E., Kagey-Sobotka, A., Norman, P.S., Radden, E.B., Rosenberg, G.L. J. Allergy Clin. Immunol. (1986) [Pubmed]
  3. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Goehler, H., Lalowski, M., Stelzl, U., Waelter, S., Stroedicke, M., Worm, U., Droege, A., Lindenberg, K.S., Knoblich, M., Haenig, C., Herbst, M., Suopanki, J., Scherzinger, E., Abraham, C., Bauer, B., Hasenbank, R., Fritzsche, A., Ludewig, A.H., Büssow, K., Buessow, K., Coleman, S.H., Gutekunst, C.A., Landwehrmeyer, B.G., Lehrach, H., Wanker, E.E. Mol. Cell (2004) [Pubmed]
  4. Synapse formation is regulated by the signaling adaptor GIT1. Zhang, H., Webb, D.J., Asmussen, H., Horwitz, A.F. J. Cell Biol. (2003) [Pubmed]
  5. The GIT-associated kinase PAK targets to the centrosome and regulates Aurora-A. Zhao, Z.S., Lim, J.P., Ng, Y.W., Lim, L., Manser, E. Mol. Cell (2005) [Pubmed]
  6. GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. Frank, S.R., Adelstein, M.R., Hansen, S.H. EMBO J. (2006) [Pubmed]
  7. Thyrotropin receptor trafficking relies on the hScrib-betaPIX-GIT1-ARF6 pathway. Lahuna, O., Quellari, M., Achard, C., Nola, S., Méduri, G., Navarro, C., Vitale, N., Borg, J.P., Misrahi, M. EMBO J. (2005) [Pubmed]
  8. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Zhao, Z.S., Manser, E., Loo, T.H., Lim, L. Mol. Cell. Biol. (2000) [Pubmed]
  9. The GIT family of ADP-ribosylation factor GTPase-activating proteins. Functional diversity of GIT2 through alternative splicing. Premont, R.T., Claing, A., Vitale, N., Perry, S.J., Lefkowitz, R.J. J. Biol. Chem. (2000) [Pubmed]
  10. The GIT family of proteins forms multimers and associates with the presynaptic cytomatrix protein Piccolo. Kim, S., Ko, J., Shin, H., Lee, J.R., Lim, C., Han, J.H., Altrock, W.D., Garner, C.C., Gundelfinger, E.D., Premont, R.T., Kaang, B.K., Kim, E. J. Biol. Chem. (2003) [Pubmed]
  11. GIT1 mediates thrombin signaling in endothelial cells: role in turnover of RhoA-type focal adhesions. van Nieuw Amerongen, G.P., Natarajan, K., Yin, G., Hoefen, R.J., Osawa, M., Haendeler, J., Ridley, A.J., Fujiwara, K., van Hinsbergh, V.W., Berk, B.C. Circ. Res. (2004) [Pubmed]
  12. Characterization of the endogenous GIT1-betaPIX complex, and identification of its association to membranes. Botrugno, O.A., Paris, S., Za, L., Gualdoni, S., Cattaneo, A., Bachi, A., de Curtis, I. Eur. J. Cell Biol. (2006) [Pubmed]
  13. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Premont, R.T., Claing, A., Vitale, N., Freeman, J.L., Pitcher, J.A., Patton, W.A., Moss, J., Vaughan, M., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  14. Identification of GIT1/Cat-1 as a substrate molecule of protein tyrosine phosphatase zeta /beta by the yeast substrate-trapping system. Kawachi, H., Fujikawa, A., Maeda, N., Noda, M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. GIT1 is a scaffold for ERK1/2 activation in focal adhesions. Yin, G., Zheng, Q., Yan, C., Berk, B.C. J. Biol. Chem. (2005) [Pubmed]
  16. GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor. Haendeler, J., Yin, G., Hojo, Y., Saito, Y., Melaragno, M., Yan, C., Sharma, V.K., Heller, M., Aebersold, R., Berk, B.C. J. Biol. Chem. (2003) [Pubmed]
  17. Phosphorylation of serine 709 in GIT1 regulates protrusive activity in cells. Webb, D.J., Kovalenko, M., Whitmore, L., Horwitz, A.F. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  18. Association of the kinesin motor KIF1A with the multimodular protein liprin-alpha. Shin, H., Wyszynski, M., Huh, K.H., Valtschanoff, J.G., Lee, J.R., Ko, J., Streuli, M., Weinberg, R.J., Sheng, M., Kim, E. J. Biol. Chem. (2003) [Pubmed]
  19. Transport and metabolism of glycerophosphodiesters produced through phospholipid deacylation. Patton-Vogt, J. Biochim. Biophys. Acta (2007) [Pubmed]
  20. Hic-5 interacts with GIT1 with a different binding mode from paxillin. Nishiya, N., Shirai, T., Suzuki, W., Nose, K. J. Biochem. (2002) [Pubmed]
  21. Interaction between liprin-alpha and GIT1 is required for AMPA receptor targeting. Ko, J., Kim, S., Valtschanoff, J.G., Shin, H., Lee, J.R., Sheng, M., Premont, R.T., Weinberg, R.J., Kim, E. J. Neurosci. (2003) [Pubmed]
  22. Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Claing, A., Perry, S.J., Achiriloaie, M., Walker, J.K., Albanesi, J.P., Lefkowitz, R.J., Premont, R.T. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  23. Regulation of neuroendocrine exocytosis by the ARF6 GTPase-activating protein GIT1. Meyer, M.Z., Déliot, N., Chasserot-Golaz, S., Premont, R.T., Bader, M.F., Vitale, N. J. Biol. Chem. (2006) [Pubmed]
  24. GIT1 functions in a motile, multi-molecular signaling complex that regulates protrusive activity and cell migration. Manabe, R., Kovalenko, M., Webb, D.J., Horwitz, A.R. J. Cell. Sci. (2002) [Pubmed]
  25. The phosphotyrosine peptide binding specificity of Nck1 and Nck2 Src homology 2 domains. Frese, S., Schubert, W.D., Findeis, A.C., Marquardt, T., Roske, Y.S., Stradal, T.E., Heinz, D.W. J. Biol. Chem. (2006) [Pubmed]
  26. Molecular weight determination of allergen extracts and isolation of allergenic molecules by high-performance liquid chromatography. Wahl, R., Meineke, D., Maasch, H.J. J. Chromatogr. (1987) [Pubmed]
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