Frank Echtermeyer and Michael Streit contributed equally to this work.Received for publication June 12, 2000, and accepted in revised form December 8, 2000.The syndecans make up a family of transmembrane heparan sulfate proteoglycans that act as coreceptors with integrins and growth factor tyrosine kinase receptors. Syndecan-4 is upregulated in skin dermis after wounding, and, in cultured fibroblasts adherent to the ECM protein fibronectin, this proteoglycan signals cooperatively with β 1 integrins. In this study, we generated mice in which the syndecan-4 gene was disrupted by homologous recombination in embryonic stem cells to test the hypothesis that syndecan-4 contributes to wound repair. Mice heterozygous or homozygous for the disrupted syndecan-4 gene are viable, fertile, and macroscopically indistinguishable from wild-type littermates. Compared with wild-type littermates, mice heterozygous or homozygous for the disrupted gene have statistically significant delayed healing of skin wounds and impaired angiogenesis in the granulation tissue. These results indicate that syndecan-4 is an important cell-surface receptor in wound healing and angiogenesis and that syndecan-4 is haplo-insufficient in these processes.
The assembly of focal adhesions and actin stress fibers by cells plated on fibronectin depends on adhesionmediated signals involving both integrins and cell-surface heparan sulfate proteoglycans. These two cell-surface receptors interact with different domains of fibronectin. To attempt to identify the heparan sulfate proteoglycans involved, we used fibronectin-null (FN؊͞؊) mouse fibroblasts to eliminate the contribution of endogenous fibronectin during the analysis.
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Signaling pathways regulating the differentiation program of epidermal cells overlap widely with those activated during apoptosis. How differentiating cells remain protected from premature death, however, is still poorly defined. We show here that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated at early stages of mouse keratinocyte differentiation both in culture and in the intact epidermis in vivo. Expression of active Akt in keratinocytes promotes growth arrest and differentiation, whereas pharmacological blockade of PI3K inhibits the expression of "late" differentiation markers and leads to death of cells that would otherwise differentiate. Mechanistically, the activation of the PI3K/Akt pathway in keratinocyte differentiation depends on the activity of the epidermal growth factor receptor and Src families of tyrosine kinases and the engagement of E-cadherin-mediated adhesion. During this process, PI3K associates increasingly with cadherin-catenin protein complexes bearing tyrosine phosphorylated YXXM motifs. Thus, the PI3K signaling pathway regulates the choice between epidermal cell differentiation and death at the cross-talk between tyrosine kinases and cadherin-associated catenins.The epidermis is a self-renewing stratified epithelium in which the loss of terminally differentiated cells from its surface is balanced by cells that leave the proliferative basal layer and enter differentiation (1, 2). Because a metabolically dead cornified cell envelope is the end point of epidermal differentiation, this process may be viewed as a specialized form of programmed cell death (3). Moreover, the apoptotic program and keratinocyte differentiation share overlapping signaling effector mechanisms (4). Notably, the caspase-3 cysteine protease, an integral component of the cell death machinery, was implicated recently in embryonic keratinocyte differentiation control downstream of Notch1 (5), and activation of the related caspase-14 has been reported during adult keratinocyte differentiation (6). Nevertheless, "canonical" apoptosis and epidermal differentiation are distinct processes, with diverse execution times and biological outcomes; the former leads to the elimination of individual dead cells from tissues within hours, whereas the latter relies on the survival and synchronized maturation of whole sheets of cells over the course of weeks. Thus, an outstanding question is how keratinocytes can activate arrays of death-inducing signals during differentiation and yet remain protected from premature death.A candidate pathway for the survival of differentiating keratinocytes is the signaling module formed by the Class IA PI3K 4 and the downstream serine-threonine kinase Akt effectors (Akt/PKB-1, -2, and -3 isoforms) (7). The PI3K family is divided into three distinct classes (Class I, II, and III) based on primary structure, substrate specificity, and mode of regulation (8). Class I PI3Ks include four distinct p110 catalytic isoforms, further divided into Class IA (-␣, -, -␦) and IB (-␥); among these, p110...
Scarring is characterized by excessive synthesis and contraction of extracellular matrix. Here, we show that fibroblasts from scarred (lesional) areas of patients with the chronic fibrotic disorder diffuse scleroderma [diffuse systemic sclerosis (dSSc)] show an enhanced ability to adhere to and contract extracellular matrix, relative to fibroblasts from unscarred (nonlesional) areas of dSSc patients and dermal fibroblasts from normal, healthy individuals. The contractile abilities of normal and dSSc dermal fibroblasts were suppressed by blocking heparin sulfate-containing proteoglycan biosynthesis or antagonizing transforming growth factor-beta receptor type I [activin-linked kinase (ALK5)] or ras/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK). Compared with both normal and nonlesional fibroblasts, lesional dSSc fibroblasts overexpressed the heparin sulfate-containing proteoglycan syndecan 4. We also found that the procontractile signals from transforming growth factor (TGF)-beta were integrated through syndecan 4 and MEK/ERK because the ability of TGFbeta to induce contraction of dermal fibroblasts was prevented by MEK antagonism. TGFbeta could not induce a contractile phenotype or phosphorylate ERK in syndecan 4(-/-) dermal fibroblasts. These results suggest that integrating TGFbeta and ERK signals via syndecan 4 is essential for the contractile ability of dermal fibroblasts. We conclude that antagonizing MEK/ERK, TGFbeta1/ALK5, or syndecan 4 may alleviate scarring in chronic fibrotic disease.
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