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Identification of novel substrates and effector pathways of the LKB1- dependent MARK kinases regulating tumorigenesis and cancer metastasis

  • Author(s): Goodwin, Jonathan M.
  • et al.
Abstract

The kinase LKB1 is a tumor suppressor mutated in familial and sporadic human cancers, whose loss is uniquely coupled with metastatic progression. LKB1 serves as the direct upstream activating kinase for a family of 13 kinases known as the AMP-activated Protein Kinase Related kinases (AMPKRs). Although LKB1 controls growth and metabolism through phosphorylation of the well-characterized family member AMPK, the relative contribution and critical substrates of the other AMPKR members in tumor suppression remain uncharacterized. Using proteomic and bioinformatic approaches, we aimed to identify novel substrates of the MARK kinase subfamily, the human homologs of Par1 with conserved roles in cell polarity, Wnt signaling, and cytoskeletal signaling. In the presented work, we have identified two novel direct substrates of the MARK kinases, DIXDC1 and ICAT, which have critical roles in the suppression of metastasis and Wnt signaling, respectively. Additionally, we have identified the morphogens Wnt5a and Wnt5b as critical mediators of migration and invasion upregulated in genetically-defined contexts of LKB1 or DIXDC1 alteration, and also upon general metastatic progression in lung cancer. Clinically, our data suggests novel treatment strategies in metastatic lung cancer, melanoma, and colorectal carcinoma. Through further identification of MARK substrates based off the determined consensus motif profiles, and additional characterization of LKB1/DIXDC1/Wnt5a in laboratory models of tumor metastasis and patient populations, we aim to decode critical downstream effector pathways of the LKB1 tumor suppressor and novel therapeutic approaches to treat patients based on defined genetic alterations

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