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The Kissil Laboratory

Research

Signaling pathway crosstalk
Over the past several years our studies have focused on crosstalk between pathways regulated by small G-proteins from the Ras family and the Notch pathways. In particular, we have focused on the role of the Notch pathways in cancers driven by the K-ras oncogene. Lung cancer is the leading cause of cancer deaths worldwide, with 5-year survival rates of <15%. Activating mutations of the K-ras gene are found in more than 30% of lung adenocarcinoma, indicating that mutant K-ras is a major driver of lung cancer. Our studies have identified signaling pathways regulated by Notch1 as potentially important therapeutic targets in non-small cell lung cancer (NSCLC). The Notch family consists of four receptors in mammals (Notch1-4) and recent studies indicate that the different Notch receptors have distinct and non-overlapping functions in tumorigenesis. We are currently employing a host of in vivo and cell culture models to dissect the role of the different Notch receptors in NSCLC and determine the viability of targeting these receptors as a therapeutic approach.

Mechanisms regulating cell proliferation

Mechanisms regulating cell proliferation

Signaling pathway crosstalk

While normal cells possess mechanisms that suppress cell proliferation when conditions are inappropriate, tumor cells can circumvent these mechanisms. One such regulatory mechanism is triggered by a stimulus known as “cell-cell contact”, when cells reach a critical number and density. This “contact-inhibition” often becomes dysregulated during tumorigenesis. Over the past several years we have focused on how ”contact-inhibition” triggers anti-proliferative/growth control signals. A central player in the process is a protein called Merlin, which is the product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is functionally inactivated in a broad range of tumors and has been shown to function as a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. And have determined that Merlin’s ability to regulate multiple downstream signaling pathways is mediated through the Angiomotins. We are working to determine how the Angiomotins function and whether the targeting these effectors might prove beneficial in the treatment of NF2.

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