Cdc42 expression in keratinocytes is required for the maintenance of the basement membrane in skin

Wu, Xunwei; Quondamatteo, Fabio; Brakebusch, Cord

doi:10.1016/j.matbio.2006.09.001

Cited by 23 publications

(12 citation statements)

References 43 publications

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“…These abnormalities grew more severe with age and corresponded to localized absence of the basement membrane in older mutant mice. 44 Intriguingly, these features are very similar to the pathology of KS skin, ie, abnormal deposition of basement membrane components, disorganized architecture of the dermal-epidermal junction, and progression of the phenotype with advancing age, 14,44 and thus support the physiological relevance of kindlin-1 in regulation of cell polarity via Cdc42.…”

Section: Discussionmentioning

confidence: 78%

Kindlin-1 Is Required for RhoGTPase-Mediated Lamellipodia Formation in Keratinocytes

Has

Herz

Зимина

et al. 2009

The American Journal of Pathology

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Kindlin-1 is an epithelial-specific member of the novel kindlin protein family, which are regulators of integrin functions. Mutations in the gene that encodes Kindlin-1, FERMT1 (KIND1), cause the Kindler syndrome (KS), a human disorder characterized by mucocutaneous fragility, progressive skin atrophy, ulcerative colitis, photosensitivity, and propensity to skin cancer. Our previous studies indicated that loss of kindlin-1 resulted in abnormalities associated with integrin functions , such as adhesion , proliferation , polarization , and motility of epidermal cells. Here , we disclosed novel FERMT1 mutations in KS and used them, in combination with small-interfering RNA, protein, and imaging studies, to uncover new functions for kindlin-1 in keratinocytes and to discern the molecular pathology of KS. We show that kindlin-1 forms molecular complexes with ␤1 integrin, ␣-actinin, migfilin, and focal adhesion kinase and regulates cell shape and migration by controlling lamellipodia formation. Kindlin-1 governs these processes by signaling via Rho family GTPases, and it is required to maintain the pool of GTP-bound, active Rac1, RhoA and Cdc42, and the phosphorylation of their downstream effectors p21-activated kinase 1, LIM kinase, and cofilin. Loss of these kindlin-1 functions forms the biological basis for the epithelial cell fragility and atrophy in the pathology of KS. (Am J

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Section: Discussionmentioning

confidence: 78%

Kindlin-1 Is Required for RhoGTPase-Mediated Lamellipodia Formation in Keratinocytes

Has

Herz

Зимина

et al. 2009

The American Journal of Pathology

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“…For the same reason, it is unlikely that the suggested function of N-WASP in polymerization of nuclear actins has an important role in transcriptional regulation, as suggested before (Wu et al, 2006a). Although mice with a keratinocyte-restricted loss of the N-WASP regulator Cdc42 formed intra-epidermal blisters (Wu et al, 2006b), and inhibition of N-WASP in Caco-2 cells interfered with the maintenance of epithelial cell junctions (Otani et al, 2006), we could not find any evidence for an important function of N-WASP in cellcell contacts of the epidermis. Also, preliminary studies on the formation of mature cell-cell junctions between N-WASP-null keratinocytes in vitro did not reveal an obvious defect (T.L.…”

Section: Discussionmentioning

confidence: 97%

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

Lefever

Pedersen

Basse

et al. 2010

Journal of Cell Science

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N-WASP is a cytoplasmic molecule mediating Arp2/3 nucleated actin polymerization. Mice with a keratinocyte-specific deletion of the gene encoding N-WASP showed normal interfollicular epidermis, but delayed hair-follicle morphogenesis and abnormal hair-follicle cycling, associated with cyclic alopecia and prolonged catagen and telogen phases. The delayed anagen onset correlated with an increased expression of the cell-cycle inhibitor p21CIP, and increased activity of the TGFβ pathway, a known inducer of p21CIP expression. Primary N-WASP-null keratinocytes showed reduced growth compared with control cells and enhanced expression of the gene encoding the cell-cycle inhibitor p15INK4B, a TGFβ target gene. Inhibition of TGFβ signaling blocked overexpression of p15INK4B and restored proliferation of N-WASP-deficient keratinocytes in vitro. However, induction of N-WASP gene deletion in vitro did not result in obvious changes in TGFβ signaling or growth of keratinocytes, indicating that the in vivo environment is required for the phenotype development. These data identify the actin nucleation regulator N-WASP as a novel element of hair-cycle control that modulates the antiproliferative and pro-apoptotic TGFβ pathway in keratinocytes in vivo and in vitro.

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“…Activated Cdc42 is recruited to adherens and tight junctions to help maintain cell-cell adhesion and establish the polarity in epithelial surfaces (Cunliffe et al , 2012; Etienne-Manneville and Hall, 2002). Keratinocytes also require Cdc42 activity for secretion of laminin 332 and maintenance of the basement membrane (Wu et al , 2006a). Therefore, as the injured skin completes its migration over the wound and re-establishes cell-cell contacts, Cdc42 activation serves several mutually beneficial purposes, which are to terminate migration while establishing a polarized epithelium that can create a new basement membrane.…”

Section: Discussionmentioning

confidence: 99%

Cdc42 Inhibits ERK-Mediated Collagenase-1 (MMP-1) Expression in Collagen-Activated Human Keratinocytes

Rohani

Pilcher

Chen

et al. 2014

Journal of Investigative Dermatology

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Following injury, keratinocytes switch gene expression programs from one that promotes differentiation to one that supports migration. A common feature of human wounds and ulcerations of any form is the expression of MMP-1 (collagenase-1) by leading-edge basal keratinocytes migrating across the dermal or provisional matrix. Induction of MMP-1 occurs by signaling from the α2β1 integrin in contact with dermal fibrillar type I collagen, and the activity of MMP-1 is required for human keratinocytes to migrate on collagen. Thus, MMP-1 serves a critical role in repair of damaged human skin. Here, we evaluated the mechanisms controlling MMP-1 expression in primary human keratinocytes from neonatal foreskin and adult female skin. Our results demonstrate that shortly following contact with type I collagen, ERK and p38 MAPK were markedly activated, whereas JNK phosphorylation remained at basal levels. ERK inhibition dramatically blocked collagen-stimulated MMP-1 expression in keratinocytes. In contrast, inhibiting p38 or JNK pathways had no effect on MMP-1 production. Moreover, investigating the role of Rho GTPases revealed that Cdc42 attenuates MMP-1 expression by suppressing ERK activity. Thus, our data indicates that injured keratinocytes induce MMP-1 expression through ERK activation, and this process is negatively regulated by Cdc42 activity.

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Cdc42 expression in keratinocytes is required for the maintenance of the basement membrane in skin

Cited by 23 publications

References 43 publications

Kindlin-1 Is Required for RhoGTPase-Mediated Lamellipodia Formation in Keratinocytes

Kindlin-1 Is Required for RhoGTPase-Mediated Lamellipodia Formation in Keratinocytes

N-WASP is a novel regulator of hair-follicle cycling that controls antiproliferative TGFβ pathways

Cdc42 Inhibits ERK-Mediated Collagenase-1 (MMP-1) Expression in Collagen-Activated Human Keratinocytes

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