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The organization and maintenance of epithelial structures relies on the integrin a6b34, which is actively involved in the formation of the hemidesmosomes that link the extracellular matrix with the intermediate filament cytoskeleton. A new study examines the function of the integrin in invasive colon carcinoma cells on laminin-1 matrices. Results show that the a6b34 integrin is involved in the formation and stabilization of lamellae and filopodia.

The alpha6beta4 integrin is shown to promote carcinoma invasion by targeting phosphoinositide-3 OH kinase (P13K) activity. Alpha6beta4 ligation stimulated more P13K activity than B1 integrin ligation. The formation of lamellae in carcinoma cells required alpha6beta4-regulated P13K activity, and the small Rac G protein is needed downstream of P13K for invasion.

Research has been conducted on small GTPase RhoB. The authors have investigated the role of RhoB in vascular development and its signaling in angiogenesis.

Examines the activation of the alpha6beta4 integrin and its association with F-actin in cell protrusions during chemotactic migration of carcinoma cells. Activation of protein kinase C-alpha; Stimulation of A431 chemotaxis; Integrin mobilization from hemidesmosomes by indirect immunofluorescence microscopy.

Presents information pertaining to the integrin ...6B4 which is a receptor for the laminins. Reinforcement of the importance of the integrin in epithelial structure; Inhibition of the formation of lamellae in cells; Indication of results.

Here we provide the first evidence that tetraspanin CD151 can support de novo carcinogenesis. During two-stage mouse skin chemical carcinogenesis, CD151 reduces tumor lag time and increases incidence, multiplicity, size, and progression to malignant squamous cell carcinoma (SCC), while supporting both cell survival during tumor initiation and cell proliferation during the promotion phase. In human skin SCC, CD151 expression is selectively elevated compared to other skin cancer types. CD151 support of keratinocyte survival and proliferation may depend on activation of transcription factor STAT3, a regulator of cell proliferation and apoptosis. CD151 also supports PKCα-α6β4 integrin association and PKC-dependent β4 S1424 phosphorylation, while regulating α6β4 distribution. CD151-PKCα effects on integrin β4 phosphorylation and subcellular localization are consistent with epithelial disruption to a less polarized, more invasive state. CD151 ablation, while minimally affecting normal cell and normal mouse functions, markedly sensitized mouse skin and epidermoid cells to chemicals/drugs including DMBA (mutagen) and camptothecin (topoisomerase inhibitor), as well as to agents targeting EGFR, PKC, Jak2/Tyk2, and STAT3. Hence, CD151 ‘co-targeting’ may be therapeutically beneficial. These findings not only support CD151 as a potential tumor target, but also should apply to other cancers utilizing CD151-laminin-binding integrin complexes.

Hemidesmosomes (HDs) are multiprotein structures that anchor epithelial cells to the basement membrane. HD components include the alpha6beta4 integrin, plectin, and BPAGs (bullous pemphigoid antigens). HD disassembly in keratinocytes is necessary for cells to migrate and can be induced by EGF through beta4 integrin phosphorylation. We have identified a novel phosphorylation site on the beta4 integrin: S(1424). Preventing phosphorylation by mutating S-->A(1424) results in increased incorporation of beta4 into HDs and resistance to EGF-induced disassembly. In contrast, mutating S-->D(1424) (mimicking phosphorylation) partially mobilizes beta4 from HDs and potentiates the disassembly effects of other phosphorylation sites. In contrast to previously described sites that are phosphorylated upon growth factor stimulation, S(1424) already exhibits high constitutive phosphorylation, suggesting additional functions. Constitutive phosphorylation of S(1424) is distinctively enriched at the trailing edge of migrating keratinocytes where HDs are disassembled. Although most of this S(1424)-phosphorylated beta4 is found dissociated from HDs, a substantial amount can be associated with HDs near the cell margins, colocalizing with plectin but always excluding BPAGs, suggesting that phospho-S(1424) might be a mechanism to dissociate beta4 from BPAGs. S(1424) phosphorylation is PKC dependent. These data suggest an important role for S(1424) in the gradual disassembly of HDs induced by cell retraction.