Domain analysis reveals striking functional differences between the regulatory subunits of phosphatidylinositol 3-kinase (PI3K), p85alpha and p85beta.

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Ito Y, Vogt PK, Hart JR

Oncotarget. 2017 Aug 3;8(34):55863-55876. doi: 10.18632/oncotarget.19866. eCollection 2017 Aug 22.

Our understanding of isoform-specific activities of phosphatidylinositol 3-kinase (PI3K) is still rudimentary, and yet, deep knowledge of these non-redundant functions in the PI3K family is essential for effective and safe control of PI3K in disease. The two major isoforms of the regulatory subunits of PI3K are p85alpha and p85beta, encoded by the genes PIK3R1 and PIK3R2, respectively. These isoforms show distinct functional differences that affect and control cellular PI3K activity and signaling [1-4]. In this study, we have further explored the differences between p85alpha and p85beta by genetic truncations and substitutions. We have discovered unexpected activities of the mutant proteins that reflect regulatory functions of distinct p85 domains. These results can be summarized as follows: Deletion of the SH3 domain increases oncogenic and PI3K signaling activity. Deletion of the combined SH3-RhoGAP domains abolishes these activities. In p85beta, deletion of the cSH2 domain reduces oncogenic and signaling activities. In p85alpha, such a deletion has an activating effect. The deletions of the combined cSH2 and iSH2 domains and also the deletion of the cSH2, iSH2 and nSH2 domains yield results that go in the same direction, generally activating in p85alpha and reducing activity in p85beta. The contrasting functions of the cSH2 domains are verified by domain exchanges with the cSH2 domain of p85beta exerting an activating effect and the cSH2 domain of p85alpha an inactivating effect, even in the heterologous isoform. In the cell systems studied, protein stability was not correlated with oncogenic and signaling activity. These observations significantly expand our knowledge of the isoform-specific activities of p85alpha and p85beta and of the functional significance of specific domains for regulating the catalytic subunits of class IA PI3K.

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