5′-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion

Invadopodia are specialized membrane protrusions that support degradation of extracellular matrix (ECM) by cancer cells, allowing invasion and metastatic spread. Although early stages of invadopodia assembly have been elucidated, little is known about maturation of invadopodia into structures competent for ECM proteolysis. The localized conversion of phosphatidylinositol(3,4,5)-triphosphate and accumulation of phosphatidylinositol(3,4)-bisphosphate at invadopodia is a key determinant for invadopodia maturation. Here we investigate the role of the 5′-inositol phosphatase, SHIP2, and reveal an unexpected scaffold function of SHIP2 as a prerequisite for invadopodia-mediated ECM degradation. Through biochemical and structure-function analyses, we identify specific interactions between SHIP2 and Mena, an Ena/VASP-family actin regulatory protein. We demonstrate that SHIP2 recruits Mena, but not VASP, to invadopodia and that disruption of SHIP2–Mena interaction in cancer cells leads to attenuated capacity for ECM degradation and invasion in vitro, as well as reduced metastasis in vivo. Together, these findings identify SHIP2 as a key modulator of carcinoma invasiveness and a target for metastatic disease

ARF6 controls RHOB targeting to endosomes regulating cancer cell invasion

Endocytic trafficking has emerged as an essential mechanism to spatiotemporally coordinate signaling protein complexes that control cytoskeletal dynamics and cell motility. Our study established an unexpected regulatory mechanism whereby ADP ribosylation factors 6 (ARF6) controls the stability and endosomal localization of RAS homologous protein B (RHOB) to regulate cell invasion downstream of the oncogenic receptor tyrosine kinase, MET

CD154 inhibits death of T cells via a Cis interaction with the α5β1 integrin.

CD154 plays a major role in the pathogenesis of several autoimmune and inflammatory diseases. In addition to CD40, soluble CD154 (sCD154) binds to other receptors namely αIIbβ3, αMβ2, α5β1 and αvβ3 integrins. We have previously reported that binding of sCD154 to α5β1 integrin expressed on several human T cell lines is capable of inhibiting Fas-induced cell death. In the current study, we show that such effect of the sCD154/α5β1 interaction is not restricted to the cell death response induced by Fas but could also be exhibited toward other death signals such as TRAIL and TNF- α. We also demonstrate that sCD154 is capable of inhibiting Fas-mediated death of human activated T cells, more importantly of CD4+ than CD8+ T ones. Our data also show that membrane-bound CD154 and α5β1 integrin expressed on the surface of distinct cells failed to influence cell death responses. However, when membrane-bound CD154 and α5β1 are expressed on the surface of same cell, their interaction was capable of down regulating cell death. CD154 was shown to co-localize with the α5β1 integrin on the surface of these cells. These data strongly suggest a cis-type of interaction between CD154 and α5β1 when both are expressed on the same cell surface, rather than a trans-interaction which usually implicates the ligand and its receptor each expressed on the surface of a distinct cell. Taken together, these findings add to the list of roles through which CD154 is contributing to the pathogenesis of autoimmune-inflammatory diseases, i.e. by protecting T cells from death and enhancing their survival

COMMD5/HCaRG Hooks Endosomes on Cytoskeleton and Coordinates EGFR Trafficking

Summary: COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is crucial for the stability of the cytoskeleton. Its silencing leads to a major re-organization of actin and microtubule networks. The N terminus of COMMD5 binds to the endosomal Rab5, and its C terminus, including the COMMD domain, binds to the cytoskeletal scaffolding. COMMD5 participates in long-range endosome transport, including epidermal growth factor receptor (EGFR) recycling, and provides the strength to deform and assist the scission of vesicles into sorting endosomes. This study establishes the molecular mechanism by which COMMD5 acts as an adaptor protein to coordinate endosomal trafficking and reveals its important role for EGFR transport and activity. : COMMD5/HCaRG is involved in endocytic trafficking. Campion et al. describe the link between COMMD5, the cytoskeletal proteins actin and tubulin, and Rab5-associated endosomes in epithelial cells. COMMD5 directly interacts with actin and tubulin at one end and Rab5 at the other end to drive membrane proteins across endosomal compartments and thereby regulate EGFR trafficking and activation and directional cell migration. Keywords: COMMD5/HCaRG, endosome trafficking, early and recycling endosomes, Rab, receptor trafficking, EGFR, tubulin, microtubule, actin, migratio