My lab investigates signaling by cell adhesion receptors, neoplastic transformation, and metastatic dissemination.
Immunoblotting shows that the activation of STAT3 and c-Jun is defective in ErbB2-transformed mammary epithelial cells carrying a knock-in mutation that deletes the c-terminal, signaling domain of the β4 integrin (left). The model illustrates the signaling mechanisms that enable β4 to amplify oncogenic ErbB2 signaling (right). See Guo et al. Cell 10:93-95, 2006.
During embryonic development, tissue morphogenesis and various repair processes, individual cells respond to contextual cues that regulate their ability to enter into and progress through the cell cycle, to migrate, and to resist pro-apoptotic insults. The integrin and cadherin adhesion receptors function in these signaling networks by imparting positional control to the action of growth factor receptor tyrosine kinases. The ability of integrins to enable mitogenic signaling (anchorage dependence) and the antithetic effect of cadherins (contact inhibition) illustrate the extraordinary control that cell adhesion exerts on the behavior of non-neoplastic cells.
Building upon the discovery of oncogenes and tumor suppressor genes, investigations on the biology of cancer have revealed that oncogenic mutations disrupt the regulatory circuits that govern cell fate, endowing tumor cells with the ability to undergo deregulated mitogenesis, to resist apoptotic insults, and to invade through tissue boundaries. This profoundly antisocial behavior of cancer cells, which culminates in metastatic colonization of distant organs, is perhaps the most defining feature of malignancy. Our prior work has provided evidence that loss of cadherin signaling and deregulated integrin signaling are necessary to propel the expansion of neoplastic cells (see “Our Areas of Interest” below and the Projects page). We are leveraging our expertise in cell adhesion and signaling to better understand various aspects of cancer.
Immunofluorescent staining shows Merlin/NF2 in the nucleus of normal Schwann cells. In response to contact inhibition or loss of matrix adhesion, Merlin is dephosphorylated and inhibits the pro-mitogenic E3 ligase CRL4-DCAF1 in the nucleus. See Li et al. Cell 140:447-90, 2010.
Our Areas of Interest