The ARFGEF IQSEC1 is a targetable scaffold controlling collective cell invasion.

ABSTRACT: The signalling pathways underpinning cell growth and migration share overlapping components but what determines whether cells grow or move, when exposed to the same extrinsic signal, is unclear. We identify that in epithelial cancer cells cultured in extracellular matrix (ECM) these molecular functions can be uncoupled when signals are transduced through alternate transcript variants of IQSEC1, an ARF GTPase Exchange Factor. IQSEC1 associates with the receptor tyrosine kinase (RTK) Met and acts as an organising centre for phosphoinositide signalling, activating ARF5- and ARF6-dependent PIP5-kinase activity, and scaffolding multiple components of the mTORC2 signalling complex to control Akt activation and cell growth. Expression of IQSEC1 variants containing extended N-terminal regions switch this output from growth to collective invasion by conferring association with the endocytic co-receptor LRP1, thereby enhancing Met internalisation and trafficking. These pro-invasive IQSEC1 variants localise the Met/LRP1/IQSEC1 signalling module to the tips of invasive protrusions to induce PI(3,4,5)P3-dependent collective invasion. Chemical or genetic inhibition of these alternate signalling modules targets growth or invasion, independently. Alternate IQSEC1-ARF GTPase signalling complexes thus control RTK signal output by influencing RTK trafficking and the balance between growth or invasion in epithelial cells. Elevated expression of this IQSEC1-ARF module occurs in prostate cancer patient metastases and predicts poor outcome. IQSEC1 may therefore represent a therapeutic vulnerability in prostate cancer cells.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Line Cell

DISEASE(S): Prostate Cancer

SUBMITTER: Sergio Lilla  

LAB HEAD: Sara Rossana Zanivan

PROVIDER: PXD013810 | Pride | 2021-02-04

REPOSITORIES: Pride