Functional interactions between phosphatase POPX2 and mDia modulate RhoA pathways

Abstract

Rho GTPases and their downstream effectors regulate changes in the actin cytoskeleton that underlie cell motility and adhesion. They also participate, with RhoA, in the regulation of gene transcription by activating serum response factor (SRF)-mediated transcription from the serum response element (SRE). SRF-mediated transcription is also promoted by several proteins that regulate the polymerization or stability of actin. We have previously identified a family of PP2C phosphatases, POPXs, which can dephosphorylate the CDC42/RAC-activated kinase PAK and downregulate its enzymatic and actin cytoskeletal activity. We now report that POPX2 interacts with the formin protein mDia1 (DIAPH1). This interaction is enhanced when mDia1 is activated by RhoA.The binding of POPX2 to mDia1 or to an mDia-containing complex greatly decreases the ability of mDia1 to activate transcription from the SRE. We propose that the interaction between mDia1 and POPX2 (PPM1F) serves to regulate both the actin cytoskeleton and SRF-mediated transcription, and to link the CDC42/RAC1 pathways with those of RhoA. Supplementary material available online at

MicroRNA-200c Represses Migration and Invasion of Breast Cancer Cells by Targeting Actin-Regulatory Proteins FHOD1 and PPM1F

“…To identify direct miR-200c target genes, the data were merged with a list of potential miR-200bc/429 targets predicted by two microRNA target prediction tools, yielding 34 candidate target genes (see Table S6 in the supplemental material). Among those, the formin homology domain-containing protein 1 (FHOD1) and Mg 2ϩ /Mn 2ϩ -dependent protein phosphatase 1F (PPM1F) were of particular interest due to their described functions in the regulation of actin cytoskeletal organization (9,10,19,46,48). The 3=-UTRs of FHOD1 and PPM1F are predicted to contain one and two miR200c target sites, respectively, which all have a high degree of conservation among mammalian species (Fig.…”

POPX2 phosphatase regulates the KIF3 kinesin motor complex

“…The SH3 domain of PIX, however, binds strongly to PAK (Manser et al, 1998), suggesting that POPX2 is in close proximity of an activator (PIX) and effector (PAK) of the Rho GTPases. POPX2 has also been shown to interact with the formin protein mDia1 and can regulate mDia1-and RhoAregulated transcription mediated by serum response factor (Xie et al, 2008). The levels of POPX2 are higher in invasive cancer (Susila et al, 2010).…”

MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9

“…21,22 Hill et al reported that Rac1 and Cdc42 activate SRF in a RhoA-independent manner 8 ; however, several studies showed a crosslink between these pathways in SRF regulation. 23,24 In megakaryocytes (MKs), the platelet precursors, reorganization of actin cytoskeleton plays a crucial role not only in MK adhesion and migration 25 but also at different stages during maturation, ie, during endomitosis, 26 demarcation membrane formation, proplatelet formation, and platelet shedding. [27][28][29][30][31][32] Recently, it has been shown that thrombopoietin (TPO) better stimulates Rho activity in immature than in mature MKs and that the Rho/ROCK pathway is a negative regulator of proplatelet formation.…”