The Tensin-3 Protein, Including its SH2 Domain, Is Phosphorylated by Src and Contributes to Tumorigenesis and Metastasis

Abstract

Summary In cell lines from advanced lung cancer, breast cancer, and melanoma, endogenous tensin-3 contributes to cell migration, anchorage-independent growth, and tumorigenesis. Although SH2 domains have not been reported previously to be phosphorylated, the tensin-3 SH2 domain is a physiologic substrate for Src. Tyrosines in the SH2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. In a mouse breast cancer model, tensin-3 tyrosines are phosphorylated in a Src-associated manner in primary tumors, and experimental metastases induced by tumor-derived cell lines depend on endogenous tensin-3. Thus, tensin-3 is implicated as a proto-oncogene regulated by Src and possessing an SH2 domain with a previously undescribed mechanism for the regulation of ligand binding.

Tensin 3 is a new partner of Dock5 that controls osteoclast podosome organization and activity

“…Consistent with our findings, tensins have not been found as part of isolated podosomes. In agreement with previous reports (Qian et al, 2009), we found that GFP-tagged tensin 3 accumulated at focal adhesions of NIH3T3 cells. By contrast, Dock5 showed a spread localization throughout the cell (Fig.…”

“…Our results suggest that, with Dock5, tensin 3 could participate in the organization of podosome into superstructures in the osteoclast. Consistent with this idea, tensin 3 can interact with p130Cas (Qian et al, 2009), another known regulator of podosome belt formation in osteoclasts (Nagai et al, 2013) that is regulated by Dock5 (Vives et al, 2011).…”

“…In particular, its role in cell migration and invasion remains controversial. In fact, tensin 3 has been described as a tumor suppressor and as an inhibitor of cell migration (Katz et al, 2007;Martuszewska et al, 2009), but tensin 3 can also be an activator of cell migration and a promoter of invasion (Qian et al, 2009;Cao et al, 2015). At the molecular level, the function of tensins is also a matter of debate.…”

“…1C,D). The association of tensin 3 with some of its partners has been shown to rely on tyrosine phosphorylation by Src (Qian et al, 2009). We investigated the effect of Src-family kinase inhibitor PP2 on the complex between Dock5 and tensin 3 in osteoclasts.…”

Focal adhesion complex proteins in epidermis and squamous cell carcinoma

“…107 Tensin-3 has been shown to be required for tumorigenesis and metastasis in a number of different cell lines, though its role in squamous cell carcinoma specifically has not been determined. 108 Finally, Zyxin is an adaptor protein containing both LIM domains and SH3 domains. Zyxin has a punctate staining in the cytoplasm of keratinocytes within the normal epidermis; however, this staining re-localizes the the edge of migrating keratinocyte sheets during wound healing.…”