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Growth factor receptor-bound protein 2 also known as Grb2, Adapter protein GRB2, Protein Ash, or SH2/SH3 adapter GRB2 is an intracellular adaptor protein involved in growth-factor mediated signal transduction and cell communication.

Crystal structure of the mammalian adaptor protein Grb2
Crystal structure of the mammalian adaptor protein Grb2

This protein is encoded by the GRB2 gene or ASH gene and is expressed in all tissues throughout mammalian development and essential for multiple cellular functions. [1][2]

GRB2 acts as an internal receptor triggering downstream signals in many cell types. The main example of GRB2 is seen in activation of the Ras pathway through association with Son of Sevenless or Sos1 and 2, a guanine nucleotide exchange factor. Activation of this pathway leads to subsequent signalling cascades to be triggered and ultimately, gene expression.

GRB2 is the mammalian homologue to Sem-5, a similar adaptor protein found in C. elegans involved in vulval development and sex myoblast migration and also Drk, found in Drosophila, involved in signal transduction.

Structure edit

GRB2 protein is 217 AA in length, encoded by the gene GRB2 (also called ASH gene) located on chromosome 17 at position 17q25.1. < ref>Matuoka K, Shibata M, Yamakawa A, Takenawa T (October 1992). "Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 9015–9. doi:10.1073/pnas.89.19.9015. PMC 50055. PMID 1384039.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)</ref>[3]

The GRB2 gene encodes six transcripts, five of which are protein coding. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene; the GRB2 form and also the GRB3-3 isoform.

The 25kDa protein consists of a SH2 domain flanked by two SH3 domains. Each domain acts specifically; the SH2 domain of GRB2 typically binds phosphorylated tyrosine sequences on receptors or scaffold proteins, with a preference for pY-X-N-X, where X is generally a hydrophobic residue such as valine. The N-terminal SH3 domain forms complex associations with proline-rich regions of other proteins and Sos, whereas the C-terminal SH3 domain binds to peptides conforming to a P-X-I/L/V/-D/N-R-X-X-K-P motif that allows it to specifically bind to proteins such as Gab-1. [4]

Function edit

Interaction in Ras pathway edit

Activation of Receptor-linked tyrosine kinases, for example, Epidermal Growth Factor Receptor (EGFR) by a ligand (e.g. Epidermal Growth Factor) results in trans phosphorylation of the receptor's cytoplasmic tyrosine residues located at the C-terminus. [5][6][7] The phosphorylated cytoplasmic tails of these receptors recruit GRB2 proteins which dock onto the phosphotyrosine residues via their SH2 domain at the plasma membrane. Guanine nucleotide exchange factor Sos binds GRB2 by forming associations with the two SH3 domains on the GRB2 protein. [8] The formation of the EGFR-GRB2-SOS complex bring Sos into range with RAS and activates Sos - GEF activity; replacing Ras-GDP with GTP, and subsequently activating the Ras signalling pathway. Ras initiates a cascade of downstream signals, such as MAP kinase and ERK1,2, which ultimately leads to the expression of genes involved in cell proliferation, differentiation and survival.

Interaction in TCR signalling edit

See: Lck

GRB2 is also expressed in lymphocytes where it plays a role in antigen receptor signalling. [9] Activation of a T-cell Receptor (TCR) by a pathogen triggers Lck, a tyrosine kinase, to phosphorylate the associated CD3 complex thereby initiating TCR signalling and subsequently activating all three MAP kinase families. It is thought GRB2 regulates Lck activity through negative feedback, playing a role in negative selection of T cells. [10] Negative selection or T-cell mediated apoptosis, is an important process ensuring a functioning immune system by removing potentially fatal auto-immune T-lymphocyctes, which are seen to have a too high affinity for self-peptide MHC complexes. It is speculated that this process involves GRB2 which downregulates the activity of Lck and thus deletes self-recognising T-cells. [11]

Misexpression edit

GRB3-3 GRB3-3 is a natural isoform of GRB2 formed as a result of a deletion in the SH2 region of the protein. Unlike GRB2, GRB3-3 does not bind phosphorylated EGFRs (since this isoform lacks the SH2 domain) but instead inhibits EGF-induced Ras-activation in a dominant fashion over GRB2. Lack of Ras pathway activation and subsequently the downstream signalling pathways has been implicated in programmed cell death. [12]


Disease edit

Human Breast Cancer

Over expression of GRB2 protein has been implicated with tumour progression. Comparison studies between normal breast epithelium and cancerous breast epithelium observed a 2-fold increase in GRB2 mRNA in breast cancer cells, due to amplification of the GRB2 locus. The upregulation of the protein and subsequently the Ras pathway may alter cell growth signalling and thus play a role in tumour formation. [13]


Death

Homozygous knock out: GRB2 has been shown to play a vital role in early embryogenesis. Embryonic studies in mice with homozygous mutations resulting in a GRB2 knock-out (GRB2 -/-)were shown to have reduced cell proliferation and normally died by day 7.5. [14]

Heterozygous knock out: Heterozygous gene knock out experiments for GRB2 result in impaired immune response by altering T-cell development. [15]

See also edit

References edit

  1. ^ Matuoka K, Shibata M, Yamakawa A, Takenawa T (October 1992). "Cloning of ASH, a ubiquitous protein composed of one Src homology region (SH) 2 and two SH3 domains, from human and rat cDNA libraries". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 9015–9. doi:10.1073/pnas.89.19.9015. PMC 50055. PMID 1384039.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  2. ^ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J (August 1992). "The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling". Cell. 70 (3): 431–42. doi:10.1016/0092-8674(92)90167-B. PMID 1322798.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  3. ^ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J (August 1992). "The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling". Cell. 70 (3): 431–42. doi:10.1016/0092-8674(92)90167-B. PMID 1322798.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  4. ^ Berry DM, Nash P, Liu SK, Pawson T, McGlade CJ (2002). "A high-affinity Arg-X-X-Lys SH3 binding motif confers specificity for the interaction between Gads and SLP-76 in T cell signaling". Curr. Biol. 12 (15): 1336–41. doi:10.1016/S0960-9822(02)01038-2. PMID 12176364.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Lowenstein, E.J.; Daly, R.J.; Batzer, A.G.; Li, W.; Margolis, B.; Lammers, R.; Ullrich, A.; Skolnik, E.Y.; Bar-Sagi, D.; Schlessinger, J. (1992). "The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling". Cell. 70 (3). UNITED STATES: 431–42. doi:10.1016/0092-8674(92)90167-B. ISSN 0092-8674. PMID 1322798. {{cite journal}}: Cite has empty unknown parameters: |lay-date= and |lay-source= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  6. ^ Wong, Lily; Deb, Tushar Baran; Thompson, Stewart A.; Wells, Alan; Johnson, Gibbes R. (1999). "A differential requirement for the COOH-terminal region of the epidermal growth factor (EGF) receptor in amphiregulin and EGF mitogenic signaling". J. Biol. Chem. 274 (13). UNITED STATES: 8900–9. doi:10.1074/jbc.274.13.8900. ISSN 0021-9258. PMID 10085134. {{cite journal}}: Cite has empty unknown parameters: |lay-date= and |lay-source= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  7. ^ Okutani, T.; Okabayashi, Y.; Kido, Y.; Sugimoto, Y.; Sakaguchi, K.; Matuoka, K.; Takenawa, T.; Kasuga, M. (1994). "Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells". J. Biol. Chem. 269 (49). UNITED STATES: 31310–4. doi:10.1016/S0021-9258(18)47424-8. ISSN 0021-9258. PMID 7527043. {{cite journal}}: Cite has empty unknown parameters: |lay-date= and |lay-source= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  8. ^ Li, N.; Batzer, A.; Daly, R.; Yajnik, V.; Skolnik, E.; Chardin, P.; Bar-Sagi, D.; Margolis, B.; Schlessinger, J. (1993). "Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling". Nature. 363 (6424). ENGLAND: 85–8. doi:10.1038/363085a0. ISSN 0028-0836. PMID 8479541. {{cite journal}}: Cite has empty unknown parameters: |lay-date= and |lay-source= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  9. ^ Buday, L.; Egan, S. E.; Rodriguez Viciana, P.; Cantrell, D. A.; Downward, J. (1994). "A complex of Grb2 adaptor protein, Sos exchange factor, and a 36-kDa membrane-bound tyrosine phosphoprotein is implicated in ras activation in T cells". J. Biol. Chem. 269 (12). UNITED STATES: 9019–23. doi:10.1016/S0021-9258(17)37070-9. ISSN 0021-9258. PMID 7510700. {{cite journal}}: Cite has empty unknown parameters: |lay-date= and |lay-source= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  10. ^ Reif, K.; Buday, L.; Downward, J.; Cantrell, D. A. (1994). "SH3 domains of the adapter molecule Grb2 complex with two proteins in T cells: the guanine nucleotide exchange protein Sos and a 75-kDa protein that is a substrate for T cell antigen receptor-activated tyrosine kinases". J. Biol. Chem. 269 (19). UNITED STATES: 14081–7. doi:10.1016/S0021-9258(17)36757-1. ISSN 0021-9258. PMID 8188688. {{cite journal}}: Cite has empty unknown parameters: |lay-source= and |lay-date= (help); Unknown parameter |month= ignored (help)CS1 maint: date and year (link)
  11. ^ Jang, I. K., Zhang, J. and Gu, H. (2009). "Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling". Immunological Reviews. 232 (1): 150–159. doi:10.1111/j.1600-065X.2009.00842.x. PMID 19909362.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ Romero F, Ramos-Morales F, Dominguez A, Rios RM, Schweighoffer F, Tocque B, Pintor-Toro JA, Fischer S, Tortolero M (1998). "Grb2 and its apoptotic isoform Grb3-3 associate with heterogeneous nuclear ribonucleoprotein C, and these interactions are modulated by poly(U) RNA". J. Biol. Chem. 273 (13): 7776–81. doi:10.1074/jbc.273.13.7776. PMID 9516488.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Daly R.J., Binder M.D., Sutherland R.L. (1994). "Overexpression of the Grb2 gene in human breast cancer cell lines". Oncogene. 1: 2723–2727.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ Jang, I. K., Zhang, J. and Gu, H. (2009). "Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling". Immunological Reviews. 232 (1): 150–159. doi:10.1111/j.1600-065X.2009.00842.x. PMID 19909362.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Jang, I. K., Zhang, J. and Gu, H. (2009). "Grb2, a simple adapter with complex roles in lymphocyte development, function, and signaling". Immunological Reviews. 232 (1): 150–159. doi:10.1111/j.1600-065X.2009.00842.x. PMID 19909362.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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