RT Journal Article
SR Electronic
T1 Assembly of novel, nuclear dimers of the PI3-Kinase regulatory subunits underpins the pro-proliferative activity of the Cdc42-activated tyrosine kinase, ACK
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 791277
DO 10.1101/791277
A1 Natasha S. Clayton
A1 Millie Fox
A1 Jose J. Vicenté-Garcia
A1 Courtney M. Schroeder
A1 Trevor D. Littlewood
A1 Jonathan I. Wilde
A1 Jessica Corry
A1 Kadalmani Krishnan
A1 Qifeng Zhang
A1 Michael J. O. Wakelam
A1 Murray J. B. Brown
A1 Claire Crafter
A1 Helen R. Mott
A1 Darerca Owen
YR 2019
UL http://biorxiv.org/content/early/2019/10/04/791277.abstract
AB The tyrosine kinase ACK is an oncogene associated with poor prognosis in human cancers. ACK promotes proliferation, in part, by contributing to the activation of Akt, the major PI3-Kinase effector. We show that ACK also regulates PI3-Kinase directly, via interactions with the PI3-Kinase regulatory subunits. ACK interacts with all five regulatory subunit isoforms and directly phosphorylates p85α, p85β, p55α and p50α on Tyr607 (or equivalent). Phosphorylation of p85β at this residue promotes cell proliferation but, counterintuitively, ACK does not stimulate PI3-Kinase catalytic activity. We show that ACK stabilizes p85α levels by promoting an interaction between the p85 nSH2 domain and pTyr607, protecting p85 from ubiquitination. We demonstrate that ACK interacts with p85α exclusively in nuclear-enriched cell fractions where the increased levels of the regulatory subunits, together with the nSH2-pTyr607 interaction, promote formation of dimeric p85. We postulate that these novel dimers undertake nuclear functions that contribute to Cdc42-ACK driven oncogenesis. We propose that ACK shapes PI3-Kinase signalling by dampening the PIP3 response, whilst continuing to drive cell proliferation through Akt activation and hereto unexplored but crucial functions of nuclear dimeric p85. These new regulatory subunit dimers represent a previously undescribed mode of regulation for PI3-Kinase and potentially reveal additional avenues for therapeutic intervention.BHBcr homologyCRIBCdc42/Rac interactive bindingEBDEGFR binding domainEGFepidermal growth factorGAPGTPase activating proteinNESNuclear export signalPIP2phosphatidylinositol 4,5-bisphosphatePIP3phosphatidylinositol (3,4,5)-trisphosphateRTKreceptor tyrosine kinaseSAMsterile alpha motifSH2Src homology 2 domainSH3Src homology 3 domainUBAubiquitin association