Proteomics

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A p85 Isoform Switch Enhances PI3K Activation on Endosomes by a MAP4- and PI3P-dependent Mechanism


ABSTRACT: PI3K is a heterodimer of p110 catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85 recruits p110 to activated receptors on membranes, p85 loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110 localizes to microtubules via MAP4, facilitating its interaction with activated receptor kinases on endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85 knock down, the residual p110 coupled predominantly to p85 exhibits enhanced recruitment with receptor tyrosine kinases to endosomes. Moreover, the p110 C2 domain binds PI3P and this interaction is also required to recruit p110 to endosomes and for PI3K/Akt signaling. Stable knockdown of p85, which mimics the reduced p85levels observed in cancer, enhances cell growth and tumorsphere formation, and these effects are abrogated by MAP4 or p85knockdown, underscoring their role in the tumor-promoting activity of p85loss.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture, Epithelial Cell

SUBMITTER: Greg Sabat  

LAB HEAD: Dr. Richard A Anderson

PROVIDER: PXD050817 | Pride | 2024-10-17

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
F001836.dat Other
F001837.dat Other
F001838.dat Other
Mock_IP_AndersonR.MGF Mgf
Mock_IP_AndersonR.mzid.gz Mzid
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Publications

A p85 isoform switch enhances PI3K activation on endosomes by a MAP4- and PI3P-dependent mechanism.

Thapa Narendra N   Chen Mo M   Cryns Vincent L VL   Anderson Richard R  

Cell reports 20240416 5


Phosphatidylinositol 3-kinase α (PI3Kα) is a heterodimer of p110α catalytic and p85 adaptor subunits that is activated by agonist-stimulated receptor tyrosine kinases. Although p85α recruits p110α to activated receptors on membranes, p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. p110α localizes to microtubules via microtubule-associated protein 4 (MAP4), facilitating its interaction with activated receptor kinases on endosomes to initia  ...[more]

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