ROCKs: multifunctional kinases in cell behaviour

Riento, Kirsi; Ridley, Anne J.

doi:10.1038/nrm1128

Cited by 1,707 publications

(1,574 citation statements)

References 141 publications

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“…Our results show that RhoA, Cdc42 and Rac1 activity is dependent on the presence of CUTL1 in Panc1 (Figure 3a) and HT1080 cell lines (data not shown). Further downstream, RhoA activation is known to stimulate actin-myosin contractility through activation of the Rho-effector ROCK (Amano et al, 1996;Riento and Ridley, 2003). ROCK activity was also enhanced in the presence of CUTL1, as assessed by an in vitro kinase assay using MYPT1 as a substrate for immunoprecipitated ROCK (Figure 3b).…”

Section: Cutl1 Modulates Src Protein Levelsmentioning

confidence: 93%

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

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Recently, we identified the homeodomain transcription factor CUTL1 as important mediator of cell migration and tumor invasion downstream of transforming growth factor b (TGFb). The molecular mechanisms and effectors mediating the pro-migratory and pro-invasive phenotype induced by CUTL1 have not been elucidated so far. Therefore, the aim of this study was to identify signaling pathways downstream of CUTL1 which are responsible for its effects on tumor cell migration. We found that the reduced motility seen after knock down of CUTL1 by RNA interference is accompanied by a delay in tumor cell spreading. This spreading defect is paralleled by a marked reduction of Src protein levels. We show that CUTL1 leads to Src protein stabilization and activation of Srcregulated downstream signaling molecules such as RhoA, Rac1, Cdc42 and ROCK. In addition, we demonstrate that CUTL1 decreases proteasome-mediated Src protein degradation, possibly via transcriptionally upregulating Cterminal Src kinase (Csk). Based on experiments using Src knockout cells (SYF), we present evidence that Src plays a crucial role in CUTL1-induced tumor cell migration. In conclusion, our findings linking the pro-invasive transcription factor CUTL1 and the Src pathway provide important new insights in the molecular effector pathways mediating CUTL-induced migration and invasion.

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Section: Cutl1 Modulates Src Protein Levelsmentioning

confidence: 93%

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

et al. 2007

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“…The above spine length phenotype was mimicked using a constitutive active RhoA (CA-RhoA) mutant and could be largely rescued by inhibiting the RhoA effector, Rho-kinase (Govek et al 2004). Rho-kinase (also called ROK or ROCK) has been well documented to play a key role in RhoA-induced actin reorganization and to mediate at least in part RhoA's effects on spine morphogenesis [69,77]. Rho-kinases appear to influence the actin cytoskeleton by acting on LIM Kinase (LIMK), myosin light chain (MLC) and/or MLC phosphatase (see fig 1).…”

Section: Oligophrenin-1mentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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“…However, several reports suggest that the AGC group of serine/threonine kinases play roles in controlling cell proliferation, differentiation, morphology, and migration; the AGC group is closely related to the SNF1 subfamily (Reyes et al, 1998;Stopka and Skoultchi, 2003;Stephenson et al, 2004;Seo et al, 2005;Young et al, 2005). Particularly RockI and RockII of this group are Rho effectors and play important roles in cell morphology and behavior (Riento and Ridley, 2003); the small GTPase Rho regulates several steps of actin dynamics (EtienneManneville and Hall, 2002). Moreover, they are demonstrated to regulate actomyosin contraction or actin bundle assembly in the epithelium for the closure of the ventral body wall Thumkeo et al, 2005).…”

Section: Omphk1 Mutant Phenotypementioning

confidence: 99%

A new serine/threonine protein kinase,Omphk1, essential to ventral body wall formation

Hirano¹,

Kanazawa

Furushima

et al. 2006

Developmental Dynamics

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Here, we report a new serine/threonine protein kinase of the SNF1 subfamily Omphk1. Two Omphk homologues exist in each vertebrate species, and one homologue exists in Drosophila and Caenorhabditis elegans; the kinase domain is highly conserved among these homologues, and several domains are conserved among vertebrate Omphk. Omphk1 expression dynamically changes in the developing central nervous system, is found ubiquitously in epidermis, and is present uniquely in several other tissues. Its expression is also found in each tissue associated with the ventral body wall closure: the primary body wall composed of primitive ectoderm and each component of the secondary body wall. Concomitantly, its null mutant exhibits omphalocele with a failure in closure of the secondary body wall. There are no apparent gross morphological defects in brain, however, despite the unique Omphk1 expression in this tissue.

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ROCKs: multifunctional kinases in cell behaviour

Cited by 1,707 publications

References 141 publications

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

CUTL1 promotes tumor cell migration by decreasing proteasome-mediated Src degradation

Rho-linked genes and neurological disorders

A new serine/threonine protein kinase,Omphk1, essential to ventral body wall formation

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