5c5s
Crystal Structure of human Myosin 9b RhoGAP domain at 2.2 angstrom
Structural highlights
DiseaseMYO9B_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry. FunctionMYO9B_HUMAN Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. May be involved in the remodeling of the actin cytoskeleton. Binds actin with high affinity both in the absence and presence of ATP and its mechanochemical activity is inhibited by calcium ions. Also acts as a GTPase activating protein on Rho. Publication Abstract from PubMedEmerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer. Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression.,Kong R, Yi F, Wen P, Liu J, Chen X, Ren J, Li X, Shang Y, Nie Y, Wu K, Fan D, Zhu L, Feng W, Wu JY J Clin Invest. 2015 Nov 3;2015. pii: 81673. doi: 10.1172/JCI81673. PMID:26529257[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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