PIP3 abundance overcomes PI3K signaling selectivity in invadopodia

Charles T. Jakubik; Claire C. Weckerly; Gerald R.V. Hammond; Anne R. Bresnick; Jonathan M. Backer

doi:10.1002/1873-3468.14273

PIP₃ abundance overcomes PI3K signaling selectivity in invadopodia

Charles T. Jakubik, Claire C. Weckerly, Gerald R.V. Hammond, Anne R. Bresnick, Jonathan M. Backer

Research output: Contribution to journal › Article › peer-review

Abstract

PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P₂. We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short-chain diC8-PIP₃ rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P₂ is SHIP2-independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP₃ conversion to PI(3,4)P₂ for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.

Original language	English (US)
Pages (from-to)	417-426
Number of pages	10
Journal	FEBS Letters
Volume	596
Issue number	4
DOIs	https://doi.org/10.1002/1873-3468.14273
State	Published - Feb 2022

Keywords

PI 3-kinase
invadopodia
matrix degradation

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1002/1873-3468.14273

Cite this

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title = "PIP3 abundance overcomes PI3K signaling selectivity in invadopodia",

abstract = "PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2. We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short-chain diC8-PIP3 rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2 is SHIP2-independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.",

keywords = "PI 3-kinase, invadopodia, matrix degradation",

author = "Jakubik, {Charles T.} and Weckerly, {Claire C.} and Hammond, {Gerald R.V.} and Bresnick, {Anne R.} and Backer, {Jonathan M.}",

note = "Publisher Copyright: {\textcopyright} 2022 Federation of European Biochemical Societies",

year = "2022",

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doi = "10.1002/1873-3468.14273",

language = "English (US)",

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AU - Jakubik, Charles T.

AU - Weckerly, Claire C.

AU - Hammond, Gerald R.V.

AU - Bresnick, Anne R.

AU - Backer, Jonathan M.

PY - 2022/2

Y1 - 2022/2

N2 - PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2. We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short-chain diC8-PIP3 rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2 is SHIP2-independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.

AB - PI3Kβ is required for invadopodia-mediated matrix degradation by breast cancer cells. Invadopodia maturation requires GPCR activation of PI3Kβ and its coupling to SHIP2 to produce PI(3,4)P2. We now test whether selectivity for PI3Kβ is preserved under conditions of mutational increases in PI3K activity. In breast cancer cells where PI3Kβ is inhibited, short-chain diC8-PIP3 rescues gelatin degradation in a SHIP2-dependent manner; rescue by diC8-PI(3,4)P2 is SHIP2-independent. Surprisingly, the expression of either activated PI3Kβ or PI3Kα mutants rescued the effects of PI3Kβ inhibition. In both cases, gelatin degradation was SHIP2-dependent. These data confirm the requirement for PIP3 conversion to PI(3,4)P2 for invadopodia function and suggest that selectivity for distinct PI3K isotypes may be obviated by mutational activation of the PI3K pathway.

KW - PI 3-kinase

KW - invadopodia

KW - matrix degradation

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