5C5S

Crystal Structure of human Myosin 9b RhoGAP domain at 2.2 angstrom

Summary for 5C5S

• Entry DOI: 10.2210/pdb5c5s/pdb
• Descriptor: Unconventional myosin-IXb (2 entities in total)
• Functional Keywords: rhogap domain, signaling protein
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cell cortex: Q13459
• Total number of polymer chains: 4
• Total formula weight: 104241.05

Authors

Yi, F.S.,Ren, J.Q.,Feng, W. (deposition date: 2015-06-22, release date: 2015-11-25, Last modification date: 2023-11-08)

Primary citation

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, J.Y.
Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression
J.Clin.Invest., 125:4407-4420, 2015

PubMed 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.

PubMed: 26529257
DOI: 10.1172/JCI81673

Experimental method

X-RAY DIFFRACTION (2.2 Å)