title: Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression.
abstract: Emerging 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.
authors.forename: Ruirui
authors.initials: R
authors.lastname: Kong
authors.forename: Fengshuang
authors.initials: F
authors.lastname: Yi
authors.forename: Pushuai
authors.initials: P
authors.lastname: Wen
authors.forename: Jianghong
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Chen
authors.forename: Jinqi
authors.initials: J
authors.lastname: Ren
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Li
authors.forename: Yulong
authors.initials: Y
authors.lastname: Shang
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Wu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000097905:Roundabout Proteins
chemical_list: D006023:Glycoproteins; D009218:Myosins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D020742:rhoA GTP-Binding Protein; D000097905:Roundabout Proteins; C113469:myosin IXB; C120566:slit protein, vertebrate; C066737:RHOA protein, human