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Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma.

ABSTRACT: Semaphorins are secreted and membrane bound proteins that regulate axon guidance through receptors Plexins and neuropilins. Plexin B1, the Semaphorin 4D receptor, is a recently described tumor suppressor protein for melanoma. We recently showed that Plexin B1 abrogates activation of the oncogenic receptor, c-Met, by its ligand, hepatocyte growth factor (HGF), in melanoma. We have now investigated the effect of Plexin B1 on integrin-dependent pp125(FAK) activation, and the small GTP-binding protein Rho, in melanoma. Integrin receptors and Rho play critical roles in melanoma progression, through regulation of migration, proliferation and apoptosis. We engineered two human melanoma cell lines expressing Plexin B1 and analyzed integrin-dependent migration, integrin-dependent pp125(FAK) activation, and Rho activity. Results show that Plexin B1 abrogates integrin-dependent migration and activation of pp125(FAK). We also show that Rho activity is significantly reduced in cells expressing Plexin B1, and that Plexin B1 suppresses HGF-dependent Rho activation.

SUBMITTER: McClelland L

PROVIDER: S-EPMC3692372 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma.

McClelland Lindy L Chen Yulin Y Soong Joanne J Kuo Ihsin I Scott Glynis G

Pigment cell & melanoma research 20101117 1

Semaphorins are secreted and membrane bound proteins that regulate axon guidance through receptors Plexins and neuropilins. Plexin B1, the Semaphorin 4D receptor, is a recently described tumor suppressor protein for melanoma. We recently showed that Plexin B1 abrogates activation of the oncogenic receptor, c-Met, by its ligand, hepatocyte growth factor (HGF), in melanoma. We have now investigated the effect of Plexin B1 on integrin-dependent pp125(FAK) activation, and the small GTP-binding prote ...[more]

PMID: 21029396

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Project description:Plexin-B1 is a single-pass transmembrane receptor. Its Rho GTPase binding domain (RBD) can associate with small Rho GTPases and can also self-bind to form a dimer. In total, more than 400 ns of NAMD molecular dynamics simulations were performed on RBD monomer and dimer. Different analysis methods, such as root mean squared fluctuation (RMSF), order parameters (S(2)), dihedral angle correlation, transfer entropy, principal component analysis, and dynamical network analysis, were carried out to characterize the motions seen in the trajectories. RMSF results show that after binding, the L4 loop becomes more rigid, but the L2 loop and a number of residues in other regions become slightly more flexible. Calculating order parameters (S(2)) for CH, NH, and CO bonds on both backbone and side chain shows that the L4 loop becomes essentially rigid after binding, but part of the L1 loop becomes slightly more flexible. Backbone dihedral angle cross-correlation results show that loop regions such as the L1 loop including residues Q25 and G26, the L2 loop including residue R61, and the L4 loop including residues L89-R91, are highly correlated compared to other regions in the monomer form. Analysis of the correlated motions at these residues, such as Q25 and R61, indicate two signal pathways. Transfer entropy calculations on the RBD monomer and dimer forms suggest that the binding process should be driven by the L4 loop and C-terminal. However, after binding, the L4 loop functions as the motion responder. The signal pathways in RBD were predicted based on a dynamical network analysis method using the pathways predicted from the dihedral angle cross-correlation calculations as input. It is found that the shortest pathways predicted from both inputs can overlap, but signal pathway 2 (from F90 to R61) is more dominant and overlaps all of the routes of pathway 1 (from F90 to P111). This project confirms the allosteric mechanism in signal transmission inside the RBD network, which was in part proposed in the previous experimental study.

Dataset Information

Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma.

Publications

Plexin B1 inhibits integrin-dependent pp125FAK and Rho activity in melanoma.

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