The β1 family of integrins has been primarily studied as a set of receptors for the extracellular matrix. In this paper, we define a novel role for α3β1 integrin in association with the tetraspanin CD151 as a component of a cell–cell adhesion complex in epithelial cells that directly stimulates cadherin-mediated adhesion. The integrin–tetraspanin complex affects epithelial cell–cell adhesion at the level of gene expression both by regulating expression of PTPμ and by organizing a multimolecular complex containing PKCβII, RACK1, PTPμ, β-catenin, and E-cadherin. These findings demonstrate how integrin-based signaling can regulate complex biological responses at multiple levels to determine cell morphology and behavior.

Key Points• A high frequency of RAS/RAF mutations and recurrent mutations in PDGFRA and JAK3 were found in relapsed multiple myeloma patients.• Patients with NRAS, but not KRAS, mutation exhibited significantly reduced sensitivity to bortezomib but not high-dose dexamethasone.Various translocations and mutations have been identified in myeloma, and certain aberrations, such as t(4;14) and del17, are linked with disease prognosis. To investigate mutational prevalence in myeloma and associations between mutations and patient outcomes, we tested a panel of 41 known oncogenes and tumor suppressor genes in tumor samples from 133 relapsed myeloma patients participating in phase 2 or 3 clinical trials of bortezomib. DNA mutations were identified in 14 genes. BRAF as well as RAS genes were mutated in a large proportion of cases (45.9%) and these mutations were mutually exclusive. New recurrent mutations were also identified, including in the PDGFRA and JAK3 genes. NRAS mutations were associated with a significantly lower response rate to single-agent bortezomib (7% vs 53% in patients with mutant vs wildtype NRAS, P 5 .00116, Bonferroni-corrected P 5 .016), as well as shorter time to progression in bortezomib-treated patients (P 5 .0058, Bonferroni-corrected P 5 .012). However, NRAS mutation did not impact outcome in patients treated with high-dose dexamethasone. KRAS mutation did not reduce sensitivity to bortezomib or dexamethasone. These findings identify a significant clinical impact of NRAS mutation in myeloma and demonstrate a clear example of functional differences between the KRAS and NRAS oncogenes. (Blood. 2014; 123(5):632-639)

Integrin receptors for the extracellular matrix and receptor tyrosine kinase growth factor receptors represent two of the major families of receptors that transduce into cells information about the surrounding environment. Wnt proteins are a major family of signaling molecules that regulate morphogenetic events. There is presently little understanding of how the expression of Wnt genes themselves is regulated. In this study, we demonstrate that α3β1 integrin, a major laminin receptor involved in the development of the kidney, and c-Met, the receptor for hepatocyte growth factor, signal coordinately to regulate the expression of Wnt7b in the mouse. Wnt signals in turn appear to regulate epithelial cell survival in the papilla of the developing kidney, allowing for the elongation of epithelial tubules to form a mature papilla. Together, these results demonstrate how signals from integrins and growth factor receptors can be integrated to regulate the expression of an important family of signaling molecules so as to regulate morphogenetic events.