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Sci. Signal., 15 March 2011
Vol. 4, Issue 164, p. ec77
[DOI: 10.1126/scisignal.4164ec77]


Structural Biology Messing with the Brakes

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Members of the class IA family of phosphoinositide 3-kinases (PI3Ks) are heterodimers of a p110 catalytic subunit and a p85-type regulatory subunit. These PI3Ks are activated by receptor tyrosine kinases; however, the p110β isoform is unusual in that it can also be activated by G protein–coupled receptors and that it can induce transformation in its wild-type form. All of the class IA isoforms have oncogenic potential, so their activity must be tightly regulated. The p85-type regulatory subunits have an inter-SH2 (iSH2) domain, which is flanked by N-terminal and C-terminal SH2 domains (termed nSH2 and cSH2, respectively). Binding of the iSH2 and nSH2 domains to p110α inhibits its catalytic activity. When an RTK is activated, a switch in binding of the p85 SH2 domains to the RTK relieves inhibition of the p110 subunit and increases PI3K activity (see commentary by Vogt). Zhang et al. found that, in addition to the nSH2 domain, the cSH2 domain of p85 inhibited the activity of the p110β PI3K isoform. Solving the structure of p110β in complex with a construct containing the iSH2 and cSH2 domains of p85 revealed that the cSH2 domain made contact with a region in the C terminus of the kinase domain of p100β. Mutation of the contact residue within the cSH2 domain of p85 led to increased PI3K signaling in cells. Inhibition of p110β by the cSH2 domain was also relieved by RTK phosphopeptides. Thus, the authors suggest that the involvement of a third "brake" on the activity of p110β, in the form of the p85 cSH2 domain, distinguishes p110β from the other p110 isoforms, which are regulated by two brakes involving the iSH2 and nSH2 domains of p85.

X. Zhang, O. Vadas, O. Perisic, K. E. Anderson, J. Clark, P. T. Hawkins, L. R. Stephens, R. L. Williams, Structure of lipid kinase p100β/p85β elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol. Cell 41, 567–578 (2011). [PubMed]

P. K. Vogt, PI3K p110β: More tightly controlled or constitutively active? Mol. Cell 41, 499–501 (2011). [PubMed]

Citation: J. F. Foley, Messing with the Brakes. Sci. Signal. 4, ec77 (2011).

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