Keratinocyte Differentiation Is Regulated by the Rho and ROCK Signaling Pathway

McMullan, Rachel; Lax, Siân; Robertson, Vicki H.; Radford, David J.; Broad, Simon; Watt, Fiona M.; Rowles, Alison; Croft, Daniel R.; Olson, Michael F.; Hotchin, Neil A.

doi:10.1016/j.cub.2003.11.050

Cited by 108 publications

(118 citation statements)

References 20 publications

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“…53 ROCK family members stimulate the ordering of the actin cytoskeleton (ROCKI) and terminal keratinocyte differentiation (ROCKII). 25,28 The expression pattern of Bcl-2 family members changes upon keratinocyte differentiation. Their role is not related to skin differentiation as such, but they participate in the control of cellular integrity upon exposure of the skin to damaging agents (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…ROCK inhibition also results in inhibition of keratinocyte terminal differentiation and an increase in keratinocyte proliferation. 28 Accordingly, ROCKII activation induced cell cycle arrest and the expression of terminal differentiation markers. These results indicate that ROCK plays a critical role in regulating the balance between proliferation and differentiation in human keratinocyte cultures.…”

Section: Cytoskeleton Rearrangementsmentioning

confidence: 99%

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Death penalty for keratinocytes: apoptosis versus cornification

et al. 2005

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Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Cytoskeleton Rearrangementsmentioning

confidence: 99%

Death penalty for keratinocytes: apoptosis versus cornification

et al. 2005

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“…In addition to the MAPK family of kinases, other candidate kinases can also regulate keratinocyte behavior (19,20). Accordingly, we next examined the extent to which Rho signaling may be involved in mediating MT1-MMP-induced pheno- A, SCC25-tet-V (V) and SCC25-tet-MT (MT) cells were plated overnight in serum-containing media, serum-starved for 24 h, and then treated with doxycycline (Dox, 2 g/ml) for 24 h. The cells were then analyzed for ␣2-␣3-, and ␤1-integrin expression by FACS analysis.…”

Section: Mt1-mmp-induced Cellular Aggregation Is Mediated By Rock1/2 mentioning

confidence: 99%

“…typic changes by using two well characterized and frequently used inhibitors (H1191 and Y27632) to block the activity of the Rho-associated kinases ROCK1 and ROCK2. ROCK1 and ROCK2 are the best-characterized downstream Rho effectors (53,54) and have been shown to play a role in the regulation of cell-cell and cell-matrix interaction (19,20). SCC25-tet-V and SCC25-tet-MT cells were pretreated with H1191 and co-treated with doxycycline.…”

Section: Mt1-mmp-induced Cellular Aggregation Is Mediated By Rock1/2 mentioning

confidence: 99%

Rho-ROCK-Myosin Signaling Meditates Membrane Type 1 Matrix Metalloproteinase-induced Cellular Aggregation of Keratinocytes

Dangi-Garimella

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Shields

et al. 2010

Journal of Biological Chemistry

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Matrix metalloproteinases (MMPs) 2 are a large family of highly conserved metalloendopeptidases with proteolytic activity directed against a variety of extracellular matrix (ECM) substrates (1-3). MMPs have been implicated in basement membrane proteolysis, activation of growth factors, and cleavage of cell-adhesion molecules. Extending mechanistic investigation to cancer biology, numerous studies have shown that MMP overexpression enhances the invasive activity of tumor cell lines (4 -6). Analysis of human disease further supports the pro-tumorigenic role of MMPs, as increased expression of these proteases in tumor samples is clinically associated with invasion, metastasis, poor prognosis, and shorter survival times (7,8). In the specific case of squamous cell carcinoma (SCC), increased expression of membrane type 1-MMP (MT1-MMP, MMP14) is associated with ECM breakdown, tissue invasion, and lymph node metastasis (8).However, several animal studies have now clearly demonstrated that multiple members of the MMP family provide a paradoxically protective effect during the relentless molecular destruction that characterizes malignant progression. MMPs may have been initially identified as potent pro-tumorigenic proteases, but their simultaneous ability to function in an opposing, anti-tumorigenic role is now equally well established (9, 10). Such data underscore both the complexity of MMP activity in cellular signaling events as well as the importance of stringently evaluating the context in which these proteases take on either an anti-tumorigenic or pro-tumorigenic role. Intriguingly, several recent studies using SCC models have begun to suggest a putative mechanism through which MMPs may be induced to function primarily as anti-tumorigenic proteases. When exposed to carcinogens, MMP3-null mice developed squamous cell skin cancers that not only grew faster but were also strikingly less differentiated than those of control animals (11). Significantly, orthotopic injection of MMP3-expressing tumor cells resulted in pronounced tumor cell differentiation (12). However, although such findings indicate that MMPs may inhibit SCC progression by promoting tumor cell differentiation, the precise mechanism through which these proteinases regulate this process has not yet been elucidated.In normal tissue keratinocyte differentiation is a complex process mediated by cell-ECM and cell-cell interactions that subsequently activate downstream signaling pathways (13-15). Specifically, among structural proteins, integrins mediate primarily cell-ECM interactions, whereas cadherins are responsible for cell-cell interactions (13). In vitro activation of integrins or inhibition of cadherins after ligation or dominant negative expression, respectively, results in negative regulation of human keratinocyte differentiation (16 -18). Furthermore, beyond structural proteins, Rho GTPases are also known to be an important component of keratinocyte differentiation pathways. Rho signaling has been shown to mediate cell-cell and cell-matrix adhesion...

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“…Skin Development and Maintenance-Mutant overexpression and inhibitor studies in cultured keratinocyte cell lines have shown that RhoA signaling is essential for regulating skin cell proliferation and differentiation (17) and cell-cell contacts (18). Different from that in MEF cells (12), keratin-5 Cre-driven rhoA deletion in keratinocytes in vivo was sufficient to reduce phosphorylation of MLC and cofilin (19).…”

Section: Signaling Role Of Rhoa Revealed By Gene Targeting In Micementioning

confidence: 99%