The SHCA adapter protein cooperates with lipoma-preferred partner in the regulation of adhesion dynamics and invadopodia formation.

ABSTRACT: SHC adaptor protein (SHCA) and lipoma-preferred partner (LPP) mediate transforming growth factor ? (TGF?)-induced breast cancer cell migration and invasion. Reduced expression of either protein diminishes breast cancer lung metastasis, but the reason for this effect is unclear. Here, using total internal reflection fluorescence (TIRF) microscopy, we found that TGF? enhanced the assembly and disassembly rates of paxillin-containing adhesions in an SHCA-dependent manner through the phosphorylation of the specific SHCA tyrosine residues Tyr-239, Tyr-240, and Tyr-313. Using a BioID proximity labeling approach, we show that SHCA exists in a complex with a variety of actin cytoskeletal proteins, including paxillin and LPP. Consistent with a functional interaction between SHCA and LPP, TGF?-induced LPP localization to cellular adhesions depended on SHCA. Once localized to the adhesions, LPP was required for TGF?-induced increases in cell migration and adhesion dynamics. Mutations that impaired LPP localization to adhesions (mLIM1) or impeded interactions with the actin cytoskeleton via ?-actinin (?ABD) abrogated migratory responses to TGF?. Live-cell TIRF microscopy revealed that SHCA clustering at the cell membrane preceded LPP recruitment. We therefore hypothesize that, in the presence of TGF?, SHCA promotes the formation of small, dynamic adhesions by acting as a nucleator of focal complex formation. Finally, we defined a previously unknown function for SHCA in the formation of invadopodia, a process that also required LPP. Our results reveal that SHCA controls the formation and function of adhesions and invadopodia, two key cellular structures required for breast cancer metastasis.

SUBMITTER: Kiepas A 

PROVIDER: S-EPMC7397114 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature