Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens

Abstract

The biological impact of Rho depends critically on the precise subcellular localization of its active, GTP-loaded form. This can potentially be determined by the balance between molecules that promote nucleotide exchange or GTP hydrolysis. However, how these activities may be coordinated is poorly understood. We now report a molecular pathway that achieves exactly this coordination at the epithelial zonula adherens. We identify an extramitotic activity of the centralspindlin complex, better understood as a cytokinetic regulator, which localizes to the interphase zonula adherens by interacting with the cadherin-associated protein, α-catenin. Centralspindlin recruits the RhoGEF, ECT2, to activate Rho and support junctional integrity through myosin IIA. Centralspindlin also inhibits the junctional localization of p190 B RhoGAP, which can inactivate Rho. Thus, a conserved molecular ensemble that governs Rho activation during cytokinesis is used in interphase cells to control the Rho GTPase cycle at the zonula adherens.

Coronin 1B supports RhoA signaling at cell-cell junctions through Myosin II

“…7 RhoA signaling is a master regulator of actomyosin cytoskeleton and thus has been implicated in a variety of morphogenetic processes. [31][32][33][34][35][36] While the role for active RhoA signaling in facilitating essential cellular processes has been wellestablished 9,[37][38][39][40][41] there are circumstances where RhoA signaling must be downregulated, either physiologically or pathologically to elicit a biological response. 41,42 Given the importance of the actomyosin cytoskeleton in positively regulating RhoA signaling, 7,[43][44][45] targeting actin-regulators such as Coronin 1B might be one of the approaches to achieve a precise spatiotemporal regulation of RhoA.…”

“…To test this hypothesis, we immunolabelled for endogenous RhoA, as we previously found that the junctional localization of RhoA requires it to be active and thus can be used as a proxy for RhoA activity. 9 We studied this in confluent MCF-7 and Caco-2 cells, expressing either control or Coronin 1B siRNA (Fig. 3A, B).…”

“…This enables junctional NMIIA to effectively maintain RhoA signaling at the ZA following activation by exchange factors, such as Ect2. 7,9 An important implication of this positive feedback network lies in the prediction that the cortical stability of NMII spatially defines where a stable RhoA zone may be established. Indeed, computational modeling suggested that NMIIA stability, relative to that of cortical RhoA itself, was an important determinant of the RhoA signaling zone.…”

“…[4][5][6] The physical coupling of actomyosin to E-cadherin adhesions results in contractile tension at junctions, which supports tissue cohesion, epithelial integrity and morphogenesis. [7][8][9][10][11][12][13] The assembly and activity of junctional actomyosin is subject to regulation by numerous cell signaling pathways. Of these, the best understood is the canonical RhoA-ROCK pathway, where ROCK mediates signaling by active, GTP-loaded RhoA, to promote NMII activity through phosphorylation of its regulatory light chain.…”

Concise Review: Mechanotransduction via p190RhoGAP Regulates a Switch Between Cardiomyogenic and Endothelial Lineages in Adult Cardiac Progenitors

“…Noren et al [39], Asnaghi et al [70] Cadherin-mediated suppression of RhoA activity is dependent on p190RhoGAP activation but no direct binding of cadherin and RhoA has been established Catenins 1) Wildenberg et al [41] p120-Catenin associates physically with intracellular domain of cadherins and also binds with p190RhoGAP which is essential for cell-cell adhesion 2) Ratheesh et al [71] a-Catenin (cadherin associated protein) binds to central spindle which in turn inhibits p190RhoGAP-B localization thus maintaining RhoA activation which is necessary for cellcell junctions in interphase epithelial cells 3) Bairukova et al [72] p190RhoGAP regulates adherens junction via p120-Catenin, thereby mediating vascular endothelial barrier protection Endothelial transcription factors…”