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Results for “Integrin alpha6beta4”

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PubMed2005

The alpha6beta4 integrin maintains the survival of human breast carcinoma cells in vivo.

The alpha6beta4 integrin has been widely implicated in carcinoma function in vitro; however, in vivo data are scarce. To determine the importance of alpha6beta4 in tumor progression, a SUM-159 breast carcinoma cell line that is essentially devoid of alpha6beta4 expression was generated using an RNA interference strategy. Loss of alpha6beta4 expression inhibits colony formation in soft agar assays, suggesting a vital role for alpha6beta4 in survival signaling and anchorage-independent growth. Orthotopic injection of the beta4-deficient cell line into the mammary fat pad of immunocompromised mice yielded significantly fewer and smaller tumors than the control cell line, revealing a role for the alpha6beta4 integrin in tumor formation. Under conditions that mimicked the in vivo environment, decreased expression of the alpha6beta4 integrin led to enhanced apoptosis as determined by the percentage of Annexin V-FITC+, PI- cells and the presence of caspase-3 cleavage products. Recombinant vascular endothelial growth factor (VEGF) significantly inhibited the cell death observed in the beta4-deficient cell line, demonstrating the importance of VEGF expression in this survival pathway. Furthermore, loss of alpha6beta4 expression leads to enhanced apoptosis and reduced expression of VEGF in breast carcinoma cells in vivo. Importantly, the specificity of alpha6beta4 in both the in vitro and in vivo assays showed that reexpression of the beta4 subunit into the beta4-deficient cell line could rescue the functional phenotype. Taken together, these data implicate the alpha6beta4 integrin in tumor formation by regulating tumor cell survival in a VEGF-dependent manner.

Apoptosis↗

PubMed1997

Modulation of myoepithelial-associated alpha6beta4 integrin in a breast cancer cell line alters invasive potential.

In normal breast, cell-stromal contact is mediated by myoepithelial cells which strongly express alpha2beta1, alpha3beta1, and alpha6beta4 integrins, while epithelial cells exhibit alpha2beta1 and alpha3beta1 integrins at cell-cell borders, but do not express alpha6beta4 integrin. Breast carcinomas consistently show down-regulation of all integrins. We have investigated the modulatory effect of stromal proteins, hormones, and transforming growth factor beta (TGF-beta) on integrin expression in breast cancer cell lines MCF-7, T47-D, and MDA-MB 231 using indirect immunofluorescence and confocal laser scanning microscopy. MCF-7 and T47-D cells displayed low levels of both alpha2beta1 and alpha3beta1 integrins, and no alpha6beta4 integrin, and this profile remained unchanged by modulatory agents. The MDA-MB 231 cells exhibited stronger staining for alpha2beta1 and alpha3beta1 integrins and focal staining for alpha6beta4 integrin under control conditions, but markedly enhanced reactivity for the alpha6beta4 complex in the presence of TGF-beta. This was associated with acquisition of a spread cellular morphology and localization of alpha6beta4 at the cell periphery in a discrete punctate distribution. There was associated enhanced expression of epiligrin, the ligand for alpha6beta4, with similar localization to the cell periphery. Cell invasion assays through a Matrigel barrier revealed significantly reduced invasive potential of TGF-beta-treated cells, an effect largely reversed following preincubation of the treated cells with anti-beta4 integrin antibody. We conclude that alpha6beta4 integrin can be up-regulated by TGF-beta and has an anti-invasive effect on MDA-MB 231 cells. In addition to alpha6beta4, MDA-MB 231 cells exhibit other myoepithelial markers including cytokeratin 14, vimentin, and weak expression of CALLA. These findings support the concept of a subgroup of breast carcinomas displaying features of myoepithelial differentiation.

Antigens, Surface↗

PubMed2001

Injury and EGF mediate the expression of alpha6beta4 integrin subunits in corneal epithelium.

Our goal was to evaluate the role of epidermal growth factor and injury on the expression of integrin subunits alpha6(alpha6) and beta4(beta4). An in vitro wound model was used to evaluate corneal wound repair and cellular migration. Primary rabbit corneal epithelial cell cultures were serum-starved and injured in the presence or absence of EGF or tyrphostin AG1478, an inhibitor of EGF receptor kinase activity. Repair was monitored morphologically and expression was analyzed using in situ hybridization and immunohistochemistry accompanied by confocal microscopy. The addition of EGF to cell cultures induced a dose-dependent increase in beta4 mRNA expression but the constitutive expression of alpha6 was several fold greater. In the wounded cultures there was a rapid change in expression at the edge of the wound that was enhanced with EGF. In our model there was an increase in beta4 and alpha6 protein in migrating cells. Changes in integrin expression were accompanied by a transient increase in activation of the EGF receptor. The addition of tyrphostin inhibited migration of cells and wound repair, the activation of the EGF receptor and phosphorylation of beta4 in the cytoplasm. These data indicate that the activation of the EGF receptor plays a critical role in the regulation of integrin receptors and the mediation of cellular migration.

Animals↗

PubMed1997

Novel ITGB4 mutations in a patient with junctional epidermolysis bullosa-pyloric atresia syndrome and altered basement membrane zone immunofluorescence for the alpha6beta4 integrin.

Immunofluorescence studies of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) have suggested abnormalities in the expression of the alpha6 beta4 integrin, an integral component of hemidesmosomes. In this study, we examined a family with two affected individuals with JEB-PA for mutations in the ITGA6 and ITGB4 genes which encode the alpha6 and beta4 integrin polypeptides, respectively. Mutation detection strategy based on PCR amplification of genomic DNA, followed by heteroduplex analysis and direct nucleotide sequencing, did not reveal sequence variants in ITGA6. Putative pathogenic mutations, however, were identified in both ITGB4 alleles. Specifically, the proband was a compound heterozygote for a 1-bp maternal deletion, 3434delT, and an 8-bp paternal deletion, 4050de18. Both mutations result in a frameshift and premature termination codon downstream from the deletion. At the protein level, immunofluorescence of the skin of the proband revealed negative staining for the integrin alpha6 and markedly reduced staining for the beta4 subunit. Thus, the results support the notion of close association of the alpha6 beta4 integrin subunits and further attest to the critical role of this integrin in providing physiologic stability to the dermal-epidermal junction.

Alleles↗

PubMed2003

Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.

Autocrine Communication↗

PubMed2001

Unique expression pattern of the alpha6beta4 integrin and laminin-5 in human prostate carcinoma.

BACKGROUND: The alpha6beta4 integrin and its ligand, laminin-5, are essential gene products for the maintenance and remodeling of a stratified epithelium. Apparent loss of polarized alpha6beta4 integrin and laminin-5 protein expression in invasive prostate cancer as compared to normal prostate glands is known to occur. It is unknown whether these alterations occur in prostatic intraepithelial neoplasia (PIN) lesions and whether this combined defect occurs in other epithelial cancers. METHODS: Human prostate tissues containing both normal, PIN, and cancerous regions and normal and cancer tissue from breast and colon were obtained at surgery and examined for beta4 integrin and laminin-5 using standard immunofluorescence staining methods. RESULTS: Both normal prostate glands and PIN lesions contain beta4 integrin and laminin-5. Prostate carcinoma was unique in that both beta4 integrin and laminin-5 expression was uniformly absent. In contrast, the beta4 integrin and its ligand, laminin-5 were detected in all of the colon carcinoma cases and in 60% of the breast carcinomas. CONCLUSIONS: The beta4 integrin and its ligand, laminin-5 are altered during the transition of PIN lesions to invasive prostate carcinoma. These data suggest the loss of these proteins during cancer progression. In both prostate and breast carcinoma, the normal expression pattern of the beta4 integrin and laminin-5 is interrupted, in contrast to the persistent beta4 integrin and laminin-5 expression detected in colon carcinoma.

Antigens, Surface↗

PubMed2003

[Expression and significance of integrin alpha6beta4 in experimental allergic neuritis].

OBJECTIVE: To investigate the expression of the integrin alpha6beta4 in experimental allergic neuritis (EAN) and the relationship of the integrin alpha6beta4 with functional states of Schwann cells (Sc) as well as the injury and repair of the myelin during EAN. METHODS: EAN was induced in Lewis rats and sciatic nerves were resected in 18 EAN and 3 normal rats. The expression of tissue integrin alpha6beta4 was analyzed during the course of EAN induction and in controls by in situ hybridization and semi-quantitative RT-PCR. RESULTS: The detection of integrin alpha6 and beta4 subunit by hybridization in situ demonstrated that expression of alpha6 subunit present no significant changes during the course of EAN, while expression of beta4 declined in the early phase, showing less positive signals than those of the control, and restored its expression in the later or recovery phase. The changes of expression of integrin alpha6 and beta4 in EAN were confirmed by semi-quantitative PT-PCR, using GAPDH as the internal standard. CONCLUSIONS: The degeneration and injury of Sc caused by inflammation affect the expression of integrin, which shows similar changes in Sc during embryogenesis, indicating alpha6beta4 may be a marker of Sc differentiation and at least an important molecule to mark the course of EAN. The expression of alpha6beta4 correlate with the injury and repair of myelin during EAN.

Animals↗

PubMed1997

Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.

We demonstrate that the alpha6beta4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha6beta4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more PI3K activity than ligation of beta1 integrins, establishing specificity among integrins for PI3K activation. Alpha6beta4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha6beta4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.

Androstadienes↗

PubMed2006

PTH-related protein upregulates integrin alpha6beta4 expression and activates Akt in breast cancer cells.

Breast cancer is the most common carcinoma that metastasizes to bone. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process in breast cancer. We have previously shown that PTHrP increases breast cancer cell proliferation, survival, migration, and pro-invasive integrin alpha6beta4 expression. To determine the role of integrin alpha6beta4 in these PTHrP-mediated effects, we utilized two strategies to modulate expression of the alpha6 and beta4 subunits in parental and PTHrP-overexpressing MDA-MB-231 and MCF-7 cells: overexpression of alpha6beta4 by transfection with constructs encoding the alpha6 and beta4 subunits, and suppression of endogenous alpha6beta4 expression by transfection with siRNAs targeting these subunits. We now show that the effects of PTHrP are mediated via upregulation of integrin alpha6beta4 expression. We also show that integrin alpha6beta4 expression is modulated at the mRNA level, indicating a transcriptional and/or post-transcriptional mechanism of action for PTHrP. PTHrP expression also increased the levels of phosphorylated Akt, with a consequent increase in the levels of phosphorylated (inactive) glycogen synthase kinase-3 (GSK-3). The role of PTHrP in breast cancer growth and metastasis may thus be mediated via upregulation of integrin alpha6beta4 expression and Akt activation, with consequent inactivation of GSK-3.

Base Sequence↗

PubMed2006

Peripheral myelin protein 22 is in complex with alpha6beta4 integrin, and its absence alters the Schwann cell basal lamina.

Peripheral myelin protein 22 (PMP22) is a tetraspan membrane glycoprotein, the misexpression of which is associated with hereditary demyelinating neuropathies. Myelinating Schwann cells (SCs) produce the highest levels of PMP22, yet the function of the protein in peripheral nerve biology is unresolved. To investigate the potential roles of PMP22, we engineered a novel knock-out (-/-) mouse line by replacing the first two coding exons of pmp22 with the lacZ reporter. PMP22-deficient mice show strong beta-galactosidase reactivity in peripheral nerves, cartilage, intestines, and lungs, whereas phenotypically they display the characteristics of tomaculous neuropathy. In the absence of PMP22, myelination of peripheral nerves is delayed, and numerous axon-SC profiles show loose basal lamina, suggesting altered interactions of the glial cells with the extracellular matrix. The levels of beta4 integrin, a molecule involved in the linkage between SCs and the basal lamina, are severely reduced in nerves of PMP22-deficient mice. During early stages of myelination, PMP22 and beta4 integrin are coexpressed at the cell surface and can be coimmunoprecipitated together with laminin and alpha6 integrin. In agreement, in clone A colonic carcinoma cells, epitope-tagged PMP22 forms a complex with beta4 integrin. Together, these data indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of SCs with the extracellular environment.

Adenocarcinoma↗

PubMed2000

Integrin alpha6beta4 as a suppressor and a predictive marker for peritoneal dissemination in human gastric cancer.

BACKGROUND & AIMS: Because alterations of integrin expression in cancers contribute to cancer cell biology, we analyzed the association between the potential for peritoneal dissemination and integrin expression. METHODS: The dissemination potential of 10 human gastric cancer cell lines in mice with severe combined immunodeficiency (SCID) was compared with the expression of various integrins. The relationship between integrin expression and peritoneal dissemination was also investigated in surgically resected gastric cancer cases. RESULTS: The level of integrin beta4 subunit expression was inversely correlated with dissemination potential. Introduction of a full-length complementary DNA (cDNA) for beta4 subunit into cancer cells showing negligible beta4 subunit expression markedly suppressed peritoneal dissemination and inhibition of endogenous integrin alpha6beta4 by introduction of a cytoplasmic domain-deleted beta4 subunit cDNA into cells showing high expression of beta4 subunit promoted peritoneal dissemination. Apoptosis, which was histologically evident in peritoneal nodules of SCID mice, was induced in the cells with high beta4 subunit expression by attachment to laminin and stimulation with growth factors in vitro. An immunohistochemical study of specimens from 120 cases of primary gastric cancer showed that patients with beta4 subunit-positive tumors exhibited peritoneal dissemination only infrequently (P < 0.0001) and had a better outcome (P < 0.01). CONCLUSIONS: These results indicate that integrin alpha6beta4 is both a suppressor and a predictive marker for peritoneal dissemination in gastric cancer.

Animals↗

PubMed1999

Protein kinase C-dependent mobilization of the alpha6beta4 integrin from hemidesmosomes and its association with actin-rich cell protrusions drive the chemotactic migration of carcinoma cells.

We explored the hypothesis that the chemotactic migration of carcinoma cells that assemble hemidesmosomes involves the activation of a signaling pathway that releases the alpha6beta4 integrin from these stable adhesion complexes and promotes its association with F-actin in cell protrusions enabling it to function in migration. Squamous carcinoma-derived A431 cells were used because they express alpha6beta4 and migrate in response to EGF stimulation. Using function-blocking antibodies, we show that the alpha6beta4 integrin participates in EGF-stimulated chemotaxis and is required for lamellae formation on laminin-1. At concentrations of EGF that stimulate A431 chemotaxis ( approximately 1 ng/ml), the alpha6beta4 integrin is mobilized from hemidesmosomes as evidenced by indirect immunofluorescence microscopy using mAbs specific for this integrin and hemidesmosomal components and its loss from a cytokeratin fraction obtained by detergent extraction. EGF stimulation also increased the formation of lamellipodia and membrane ruffles that contained alpha6beta4 in association with F-actin. Importantly, we demonstrate that this mobilization of alpha6beta4 from hemidesmosomes and its redistribution to cell protrusions occurs by a mechanism that involves activation of protein kinase C-alpha and that it is associated with the phosphorylation of the beta4 integrin subunit on serine residues. Thus, the chemotactic migration of A431 cells on laminin-1 requires not only the formation of F-actin-rich cell protrusions that mediate alpha6beta4-dependent cell movement but also the disruption of alpha6beta4-containing hemidesmosomes by protein kinase C.

Actins↗

PubMed2004

Bacterial heat shock protein 60 may increase epithelial cell migration through activation of MAP kinases and inhibition of alpha6beta4 integrin expression.

Exogenous heat shock proteins may modify cell behavior of infected epithelium. The effect of heat shock protein 60 (hsp60) of Actinobacillus actinomycetemcomitans and Escherichia coli, and human recombinant hsp60 on migration of HaCaT skin keratinocytes was studied using the Boyden chamber assay. Hsp60 from different species increased cell migration by two- to fivefold and this effect was inhibited by ERK inhibitor PD 98059, p38 inhibitor SB 203580, and a function-blocking epidermal growth factor receptor (EGFR) antibody. Hsp60 reduced the expression of alpha6-integrin mRNA and its protein levels on the cell surface but had no effect on the expression of beta4, beta1, alpha1, alpha5 or alphav integrin subunits. Hsp60 also significantly inhibited cell adhesion to laminin-5, a ligand of alpha6beta4 integrin. These results suggest that exogenous hsp60 released from bacteria or inflammatory cells may promote epithelial cell migration through activation of EGFR and MAP kinases, and inhibition of alpha6beta4 integrin expression.

Animals↗

PubMed2001

A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth.

alpha6beta4 integrin and the Met receptor for HGF have been shown independently to promote invasive growth. We demonstrate here that Met selectively associates with alpha6beta4. In carcinoma cells expressing Met alone, HGF does not exert significant biological effects. Ectopic expression of alpha6beta4 restores HGF-regulated processes. Following Met activation, alpha6beta4 is tyrosine phosphorylated and combines with Shc and PI3K, generating an additional signaling platform that potentiates HGF-triggered activation of Ras- and PI3K-dependent pathways. In the presence of an alpha6beta4 mutant defective for Shc recruitment, Met cannot sustain HGF-mediated responses. Surprisingly, a truncated beta4 unable to bind laminins retains the activity of wild-type alpha6beta4. Such findings invoke an unexpected role for alpha6beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device.

Adaptor Proteins, Signal Transducing↗

PubMed1996

A function for the integrin alpha6beta4 in the invasive properties of colorectal carcinoma cells.

Expression of the integrin alpha6beta4, a receptor for the laminin family of matrix proteins, has been correlated with the progression and metastatic potential of several different tumors, including colorectal carcinoma. For this reason, defining the mechanistic contribution of alpha6beta4 to the aggressive behavior of colorectal and other carcinoma cells is an issue of timely importance for cancer biology. In the present study, we sought to gain insight into the function of alpha6beta4 in colorectal carcinoma cells by studying the behavior of clone A cells, which express high surface levels of this integrin, and by restoring alpha6beta4 expression in RKO cells, a beta4-deficient rectal carcinoma cell line. The data obtained reveal that alpha6beta4 expression increases the adhesive strength of these cells on laminin-1 matrices, although it does not increase their ability to migrate on such matrices. The RKO/beta4 transfectants were considerably more spread on Matrigel, laminin-1, and collagen I than the mock transfectants and displayed numerous extensions suggestive of pseudopodia. More importantly, we discovered that expression of alpha6beta4 facilitates the ability of colorectal carcinoma cells to invade both Matrigel and collagen I matrices. The alpha6beta4-dependent increases in adhesion and invasion, as well as the observed morphological changes, required an intact beta4 cytoplasmic domain. These data argue for a ligand-independent role for alpha6beta4 in promoting cell invasion, and they have important implications for the involvement of this integrin in colorectal carcinoma progression.

Antigens, Neoplasm↗

PubMed1999

Division of labor among the alpha6beta4 integrin, beta1 integrins, and an E3 laminin receptor to signal morphogenesis and beta-casein expression in mammary epithelial cells.

Contact of cultured mammary epithelial cells with the basement membrane protein laminin induces multiple responses, including cell shape changes, growth arrest, and, in the presence of prolactin, transcription of the milk protein beta-casein. We sought to identify the specific laminin receptor(s) mediating the multiple cell responses to laminin. Using assays with clonal mammary epithelial cells, we reveal distinct functions for the alpha6beta4 integrin, beta1 integrins, and an E3 laminin receptor. Signals from laminin for beta-casein expression were inhibited in the presence of function-blocking antibodies against both the alpha6 and beta1 integrin subunits and by the laminin E3 fragment. The alpha6-blocking antibody perturbed signals mediated by the alpha6beta4 integrin, and the beta1-blocking antibody perturbed signals mediated by another integrin, the alpha subunit(s) of which remains to be determined. Neither alpha6- nor beta1-blocking antibodies perturbed the cell shape changes resulting from cell exposure to laminin. However, the E3 laminin fragment and heparin both inhibited cell shape changes induced by laminin, thereby implicating an E3 laminin receptor in this function. These results elucidate the multiplicity of cell-extracellular matrix interactions required to integrate cell structure and signaling and ultimately permit normal cell function.

Animals↗

PubMed2000

The tetraspanin CD9 associates with the integrin alpha6beta4 in cultured human epidermal keratinocytes and is involved in cell motility.

Integrins are involved in several ways in keratinocyte physiology, including cell motility. CD9 is a member of the tetraspanin protein family which is found in association with other transmembrane proteins like the integrins. CD9 is expressed in the epidermal tissue, but this expression is not regulated by differentiation. The present work focuses on association of CD9 with the integrin alpha6beta4 in keratinocytes. In vivo, CD9 does not co-localize with alpha6beta4, and is not internalized with the integrin upon basal detachment with dispase. In vitro, CD9 is found partly in co-localization with alpha6beta4 and is internalized with the integrin after keratinocyte detachment with dispase. Using blocking antibodies in a phagokinetic tracks assay, we show that CD9, and to a lesser extent alpha6beta4, but not the tetraspanin CD82, promote motility of subconfluent keratinocytes on collagen I. Our observations also suggest that CD9 is involved in the formation of lamellipodia. We also report that the phorbol ester TPA has no effect on CD9 expression and association with alpha6beta4, but increases keratinocyte motility, possibly through modulation of integrin subunits expression, or through upregulation of collagenase-1 expression. Together, these results confirm that CD9 associates with alpha6beta4 in cultured keratinocytes, possibly in order to regulate the function of the integrin, and that CD9 is involved in keratinocyte motility on collagen. The data suggest that regulation of adhesion characteristics by CD9 in keratinocytes may play a role in epidermal repair.

Adult↗

PubMed1997

The coupling of alpha6beta4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation.

The signaling pathways linking integrins to nuclear events are incompletely understood. We have examined intracellular signaling by the alpha6beta4 integrin, a laminin receptor expressed in basal keratinocytes and other cells. Ligation of alpha6beta4 in primary human keratinocytes caused tyrosine phosphorylation of Shc, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. In contrast, ligation of the laminin- and collagen-binding integrins alpha3beta1 and alpha2beta1 did not cause these events. While the stimulation of Erk by alpha6beta4 was suppressed by dominant-negative Shc, Ras and RhoA, the activation of Jnk was inhibited by dominant-negative Ras and Rac1 and by the phosphoinositide 3-kinase inhibitor Wortmannin. Adhesion mediated by alpha6beta4 induced transcription from the Fos serum response element and promoted cell cycle progression in response to mitogens. In contrast, alpha3beta1- and alpha2beta1-dependent adhesion did not induce these events. These findings suggest that the coupling of alpha6beta4 integrin to the control of cell cycle progression mediated by Shc regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.

3T3 Cells↗