p-5Y-GAB in the RET-GRB2-GAB complexes binds p85-PI3K

Stable Identifier
Reaction [omitted]
Homo sapiens
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Following recruitment and phosphorylation of GAB1 or GAB2 to the RET complex, it binds the p85 subunit of p85-containing PI3 kinase (p85-PI3K), resulting in its activation (Murakami et al. 1999, Hayashi et al. 2000, Besset et al. 2000). p85-PI3K consists of a p85 adaptor subunit, which contains one Src homology 3 (SH3) and two Src homology 2 (SH2) domains, and a p110 subunit that has catalytic activity (Kapeller & Cantley 1994). These subunits are tightly associated (Carpenter et al. 1990). Though p85-PI3K can be phosphorylated, it is binding of the p85 SH2 domains that activates the enzyme (Rordorf-Nikolic et al. 1995).

GAB2 has three tyrosine residues, Y452, Y476 and Y584, which are involved in p85-PI3K binding (Crouin et al. 2001, Maus et al. 2009). GAB1 also becomes tyrosine phosphorylated and directly associates with p85 when transducing signals from receptor tyrosine kinases to p85 (Holgado-Madruga et al. 1997, Mattoon et al. 2004). There are three potential binding sites for p85 on GAB1 (Y447, Y472, and Y589) (Holgado-Madruga et al. 1997). Phosphorylation at these sites in GAB1 is represented in this reaction as a likely prerequisite for p85 binding, but this is not experimentally confirmed, hence this reaction is displayed as an uncertain event.

Literature References
PubMed ID Title Journal Year
10995764 Signaling complexes and protein-protein interactions involved in the activation of the Ras and phosphatidylinositol 3-kinase pathways by the c-Ret receptor tyrosine kinase

Besset, V, Scott, RP, Ibáñez, CF

J. Biol. Chem. 2000
11002419 Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor

Hayashi, H, Ichihara, M, Iwashita, T, Murakami, H, Shimono, Y, Kawai, K, Kurokawa, K, Murakumo, Y, Imai, T, Funahashi, H, Nakao, A, Takahashi, M

Oncogene 2000
10448070 Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation

Murakami, H, Iwashita, T, Asai, N, Shimono, Y, Iwata, Y, Kawai, K, Takahashi, M

Biochem. Biophys. Res. Commun. 1999
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