An EGFR/Src-dependent ß4 integrin/FAK complex contributes to malignancy of breast cancer.

ß4 integrin and focal adhesion kinase (FAK) are often associated with a poor prognosis in cancer patients, and their signaling events have recently been linked to malignant outcomes. Here, we demonstrate, for the first time, physical and functional interactions between ß4 integrin and FAK that influence breast cancer malignancy. An amino-terminal linker within FAK is essential for its binding with the cytodomain of ß4 integrin. Moreover, EGFR/Src-signaling triggers the tyrosine phosphorylation of ß4 integrin, which, in turn, recruits FAK to ß4 integrin and leads to FAK activation and signaling. Upon disruption of the ß4 integrin/FAK complex, tumorigenesis and metastasis in triple-negative breast cancer were markedly reduced. Importantly, the concomitant overexpression of ß4 integrin and FAK significantly correlates with malignant potential in patients with triple-negative breast cancer. This study describes a pro-metastatic EGFR/Src-dependent ß4 integrin/FAK complex that is involved in breast cancer malignancy and is a novel therapeutic target for triple-negative breast cancer.

Integrin α3ß1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt.

The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin-extracellular matrix interactions. The laminin (LM)-binding integrin α3ß1 is crucial for this developmental program; however, the LM types and LM/integrin α3ß1-dependent signaling pathways are poorly defined. We show that α3 chain-containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin α3ß1-dependent collecting duct cell functions. We demonstrate that integrin α3ß1-mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin ß1 subunit and regulator of integrin α3ß1-dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin α3-null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin α3ß1-dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways.

Sorting nexin 31 binds multiple ß integrin cytoplasmic domains and regulates ß1 integrin surface levels and stability.

Trafficking of α5ß1 integrin to lysosomes and its subsequent degradation is influenced by ligand occupancy and the binding of SNX17 via its protein 4.1, ezrin, radixin, moesin (FERM) domain to the membrane-distal NPxY motif in the cytoplasmic domain of ß1 integrin in early endosomes. Two other sorting nexin (SNX) family members, namely SNX27 and SNX31, share with SNX17 next to their obligate phox domain a FERM domain, which may enable them to bind ß integrin tails. Here we report that, in addition to SNX17, SNX31 but not SNX27 binds several ß integrin tails in early endosomes in a PI3 (phosphatidylinositide 3)-kinase-dependent manner. Similarly like SNX17, binding of SNX31 with ß1 integrin tails in early endosomes occurs between the FERM domain and the membrane-distal NPxY motif in the ß1 integrin cytoplasmic domain. Furthermore, expression of SNX31 rescues ß1 integrin surface levels and stability in SNX17-depleted cells. In contrast to SNX17, expression of SNX31 is restricted and found highly expressed in bladder and melanoma tissue. Altogether, these results demonstrate that SNX31 is an endosomal regulator of ß integrins with a restricted expression pattern.