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Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase.

ABSTRACT: Semaphorins and plexins are implicated in the progression of various types of cancer, although the molecular basis has not been fully elucidated. Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor ? (RhoGDI?), a negative regulator of RhoGTPases that blocks guanine nucleotide exchange and sequesters them away from the plasma membrane. Glioma cells challenged with Sema5A indeed showed a marked reduction in Rac1-GTP levels by 60%, with a concomitant disruption of lamellipodia. The inactivation of Rac1 was corroborated to contribute to the impediment of glioma cell invasion by Sema5A, as supported by the abolishment of effect upon forced expression of a constitutively active Rac1 mutant. Furthermore, silencing the endogenous expression of RhoGDI? in glioma cells was found to be sufficient in abrogating the down-regulation of Rac1-GTP and the ensuing suppression of glioma cell motility induced by Sema5A. Mechanistically, we provide evidence that Sema5A promotes Rac1 recruitment to RhoGDI? and reduces its membrane localization in a plexin-B3-dependent manner, thereby preventing Rac1 activation. This represents a novel signaling of semaphorin and plexin in the control of cell motility by indirect inactivation of Rac1 through RhoGDI?.

SUBMITTER: Li X

PROVIDER: S-EPMC2952245 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase.

Li Xinhua X Lee Alan Yiu Wah AY

The Journal of biological chemistry 20100809 42

Semaphorins and plexins are implicated in the progression of various types of cancer, although the molecular basis has not been fully elucidated. Here, we report the expression of plexin-B3 in glioma cells, which upon stimulation by its ligand Sema5A results in significant inhibition of cell migration and invasion. A search for the underlying mechanism revealed direct interaction of plexin-B3 with RhoGDP dissociation inhibitor α (RhoGDIα), a negative regulator of RhoGTPases that blocks guanine n ...[more]

PMID: 20696765

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Project description:The Plexins family of proteins are well-characterized transmembrane receptors of semaphorins, axon guidance cue molecules, that mediate the cell attraction or repelling effects for such cues. Plexins and their ligands are involved in numerous cellular activities, such as motility, invasion, and adhesion to the basement membrane. The detachment of cells and the gain in motility and invasion are hallmarks of the cancer metastasis cascade, thus generating interest in exploring the role of plexins in cancer metastasis. Semaphorin-plexin complexes can act as tumor promoters or suppressors, depending upon the cancer type, and are under investigation for therapeutic purposes. Our group has identified Semaphorin-5A (SEMA5A)/Plexin-B3 as an attractive targetable complex for pancreatic cancer (PC) metastasis. However, our understanding of the Plexin-B3 function and pathological expression in PC is limited, and our present study delineates the role of Plexin-B3 in PC malignancy. We examined the pathological expression of Plexin-B3 in PC tumors and metastasis using a human tissue microarray, disease progression model of PDX-Cre-Kras(G12D) (KC) mice, and different metastatic sites obtained from the KrasG12D; Trp53R172H; Pdx1-Cre (KPC) mice model. We observed a higher Plexin-B3 expression in PC tumor cores than the normal pancreas, and different metastatic sites were positive for Plexin-B3 expression. However, in the KC mice model, the Plexin-B3 expression increased initially and then decreased with the disease progression. Next, to evaluate the functional role of Plexin-B3, we utilized T3M-4- and CD18/HPAF-Control and -Plexin B3 knockdown cells for different in vivo and in vitro studies. The knockdown of Plexin-B3 enhanced the in vitro cellular migration, invasiveness, and impaired colony formation in three-dimensional culture, along with an increase in cellular spread and remodeling of the actin filaments. We also observed a higher metastasis in nude mice injected with T3M-4- and CD18/HPAF-shPlexin-B3 cells compared to their respective control cells. Furthermore, we observed a lower number of proliferating Ki-67-positive cells and higher ALDH1-A1-positive cells in the tumors formed by Plexin-B3 knockdown cells compared to tumors formed by the control cells. Together, our data suggest that the loss of Plexin-B3 is associated with the interference of cell division machinery and the induction of stem cell-like characteristics in PC cells.

Dataset Information

Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase.

Publications

Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDIalpha-mediated inactivation of Rac1 GTPase.

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