Regulation of autophagosome formation by Rho kinase

Mleczak, Andrzej; Millar, Sarah Y.; Tooze, Sharon A.; Olson, Michael F.; Chan, Edmond Y W

doi:10.1016/j.cellsig.2012.09.010

Cited by 51 publications

(50 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings supported our working hypothesis. Another recent report showed a novel role for ROCK in the control of autophagy (Mleczak et al, 2012), indicating that activation of autophagy by ROCK appears to be a critical step in the signaling cascade that leads to the synaptic genes changes underlying the synaptic loss. Our future experiments in vitro with manipulated ROCK expression will aim to provide more direct evidence showing that the Aβ-induced alteration of ROCK causally links to autophagy and synaptic loss.…”

Section: Discussionmentioning

confidence: 99%

β-Asarone prevents autophagy and synaptic loss by reducing ROCK expression in asenescence-accelerated prone 8 mice

et al. 2014

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

β-Asarone prevents autophagy and synaptic loss by reducing ROCK expression in asenescence-accelerated prone 8 mice

et al. 2014

View full text Add to dashboard Cite

“…Conversely, Rho signaling has also been implicated in the regulation of autophagy (92, 93). Chan et al identified Rho-associated kinase 1 (ROCK1), a downstream effector of Rho, as a regulator of starvation-induced but not basal autophagy (92).…”

Section: Autophagy and Cell Motilitymentioning

confidence: 99%

Autophagy in cancer metastasis

2016

View full text Add to dashboard Cite

Autophagy is a highly conserved self-degradative process that plays a key role in cellular stress responses and survival. Recent work has begun to explore the function of autophagy in cancer metastasis, which is of particular interest given the dearth of effective therapeutic options for metastatic disease. Autophagy is induced upon progression of various human cancers to metastasis and together with data from genetically engineered mice and experimental metastasis models, a role for autophagy at nearly every phase of the metastatic cascade has been identified. Specifically, autophagy has been shown to be involved in modulating tumor cell motility and invasion, cancer stem cell viability and differentiation, resistance to anoikis, epithelial-to-mesenchymal transition, tumor cell dormancy and escape from immune surveillance, with emerging functions in establishing the pre-metastatic niche and other aspects of metastasis. In this review, we provide a general overview of how autophagy modulates cancer metastasis and discuss the significance of new findings for disease management.

show abstract

“…ROCK1 phosphorylates Beclin-1 to induce autophagy under stress conditions and has also been shown to regulate the size of autophagosomes. 100,101 Because of these dual roles in regulating survival and/or apoptosis, ROCK expression levels and associated regulators of actin-myosin contractility would be expected to have the potential to be increased or decreased in different cancers. Consistent with this possibility, LIMK2, which is a downstream effector of ROCK signaling, was found to be significantly and progressively downregulated in human colorectal cancer as a result of promoter methylation.…”

Section: Apoptosismentioning

confidence: 99%

Rho-associated coiled-coil containing kinases (ROCK)

2014

View full text Add to dashboard Cite

In humans, ROCK1 and ROCK2 both contain 33 exons and are located on chromosome 18 (18q11.1) and 2 (2p24) respectively. The ROCK1 open reading frame encodes 1354 amino acids, whereas ROCK2 encodes 1388 amino acids. ROCK2 also has a reported splice variant, preferentially expressed in skeletal muscle, which results in the inclusion of 57 additional amino acids. 7 The two ROCK homologs shares 64% identity in their primary amino acid sequences, with the highest homology (92%) within the kinase domains and the coiled-coil domains being the most diverse (55%). 5 The kinase domains of ROCK are closely related to many homologous domains in this family, including dystrophia myotonica protein kinase (DMPK), myotonic dystrophy kinase related-Cdc42 related kinases (MRCK) α and β, and citron Rho-interacting kinase (CRIK) . To date, the crystal structures of the kinase domains from ROCK1, 8 ROCK2, 9 MRCKβ, 10 and DMPK 11 have been determined, which has highlighted the high degree of tertiary as well as primary similarity. N-terminal and carboxyl-terminal extensions of the ROCK kinase domains are essential for catalytic activity. 4,8,9 The ROCK kinase domains are located in the N-terminal region, which is followed by a central ~600 amino acid long amphipathic α-helix forming a coiledcoil region (Fig. 1).12 At the carboxyl-terminal region, there is a split pleckstrin homology (PH) domain, which is bisected by an internal cysteine-rich zinc finger-like motif domain (CRD). The two separate PH portions assemble together to form a typical PH domain that is attached by two short linkers to a separate CRD. 13The canonical Rho binding domain (RBD) forms a parallel coiled coil dimer, as revealed by crystal structure determinations, and binds exclusively to the switch I and switch II regions of GTP-bound active RhoA and RhoC.14,15 Two additional Rhointeracting domains were identified that can tightly interact with RhoA, which may cooperatively contribute to binding. 16 Crystal structure studies revealed that ROCK has two dimerization domains: the ~70 residue N-terminal dimerization region 8,9 and the coiled-coil helical regions.12 Charged residues in the coiled-coil might function as a hinge that allows the N-terminal kinase domains to interact with C-terminal inhibitory regions. Structural determination of full-length ROCK protein crystals will ultimately reveal how the various domains interact and the mechanism of auto-inhibition. Regulation of ROCK ActivityAlthough ROCK1 and ROCK2 have highly related functional domains and significant amino acid identity, they are regulated both by common means as well as mechanisms unique to ROCK1 or ROCK2.

show abstract

Regulation of autophagosome formation by Rho kinase

Cited by 51 publications

References 34 publications

β-Asarone prevents autophagy and synaptic loss by reducing ROCK expression in asenescence-accelerated prone 8 mice

β-Asarone prevents autophagy and synaptic loss by reducing ROCK expression in asenescence-accelerated prone 8 mice

Autophagy in cancer metastasis

Rho-associated coiled-coil containing kinases (ROCK)

Contact Info

Product

Resources

About