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.

Inhibition of KLF5–Myo9b–RhoA Pathway–Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm

“…Although RhoA mediates stress fiber formation and generates contractile forces that are required for the retraction of the trailing edge during cell migration, 33 numerous studies show that the activation of RhoA products enhances the development of actin stress fibers and impairs the migration of cancer cells. 36 Although these observations are consistent with our results, recent studies suggest tumor-suppressive roles of RhoA in human lung cancer and T cell lymphoma. 36,37 In addition, the blockade of RhoA signaling significantly increased podosome formation in myeKlf5 −/− macrophages, suggesting KLF5-independnet podosome formation.…”

“…36 Although these observations are consistent with our results, recent studies suggest tumor-suppressive roles of RhoA in human lung cancer and T cell lymphoma. 36,37 In addition, the blockade of RhoA signaling significantly increased podosome formation in myeKlf5 −/− macrophages, suggesting KLF5-independnet podosome formation. Indeed, Mark Schramp et al 38 reported that ERK5 promotes Src-induced podosome formation in Src-transformed fibroblasts by limiting Rho activation.…”

Structural Basis for the Specific Recognition of RhoA by the Dual GTPase-activating Protein ARAP3

“…It is notable that the K cat values are comparable (the biggest difference is 2-fold) and the K m values are the main factor for the differences of the catalytic efficiencies, further proving that ARAP3-RhoGAP chooses its specific target mainly through binding affinity. The same molecular mechanism for the specificity of RhoGAP activity was reported for the Myo9b-RhoGAP domain (29). As shown in Fig.…”

Slit-Robo signaling

“…Robo1-srGAP1 signaling also stimulates the infiltration of peripheral immune cells into the brain in a rat model of neuroinflammation, an effect that could be alleviated by application of Slit2 (Sherchan et al, 2016), which suggests promising potential for therapeutic approaches. Recently, another RhoA-GAP, Myo9b, was shown to bind directly to the intracellular domain of Robo1 (Kong et al, 2015), leading to Myo9b inhibition and, in this context, the inhibition of lung cancer cell migration and invasion.…”