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Review
. 2006 Apr;26(8):2877-86.
doi: 10.1128/MCB.26.8.2877-2886.2006.

Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis

Kevin Wilhelmsen  1 , Sandy H M Litjens, Arnoud Sonnenberg
Affiliations
Review

Multiple functions of the integrin alpha6beta4 in epidermal homeostasis and tumorigenesis

Kevin Wilhelmsen et al. Mol Cell Biol. 2006 Apr.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Structure of the integrin α6β4. The structures of the α6 and β4 subunits are depicted. The positions of important tyrosine residues reported in the literature and the locations of the regions that are critical for the association with other hemidesmosomal components are shown. The yellow cylinders depict the four FNIII domains, numbered in ascending order from the plasma membrane, and the pink cylinder shows the location of the CalX motif.
FIG. 2.
FIG. 2.
Model of the hierarchical assembly of HDs. After the CS of β4 becomes dephosphorylated by an unidentified phosphatase, the plectin ABD is free to make associations with the first pair of FNIII domains on β4. The interaction of β4 and plectin is enforced by additional interactions between the plectin plakin domain and the β4 CS and the C-tail, which results in the formation of a type II HD. Once plectin is bound, BP180 is recruited into the complex, which makes associations with both the third FNIII domain of β4 and plectin. Lastly, a type I HD is formed once BP230 becomes incorporated into the complex through associations to both β4 and BP180. BP230 and plectin both can bind to IFs through an interaction site at their respective C termini.
FIG. 3.
FIG. 3.
In vitro carcinoma cell invasion. The various signaling pathways reported for α6β4-dependent invasion of carcinoma cells are shown. EGF receptor- and c-met-dependent invasion pathways rely upon the activation of PI-3 kinase, as does MAb cross-linking of the β4 subunit. Under hypoxic conditions, the upregulation of Rab11 results in the increased surface expression of α6β4, which has been reported to enhance invasion. Activation of α6β4 can also increase the extracellular expression of autotoxin, which results in the production of the proinvasive protein stearoly-lysophosphatidic acid (sLPA). PTK, protein-tyrosine kinase; LPC, lysophosphatidylcholine.
FIG. 4.
FIG. 4.
In vitro carcinoma and tumor cell survival. Three major α6β4-dependent cancer cell survival mechanisms have been reported. Carcinoma survival has been reported to depend on the upregulation of VEGF downstream of tyrosine 1494 in β4. Exocytosis of VEGF results in the activation of its receptor, which leads to carcinoma survival through activation of the PI-3 kinase/Akt survival pathway. Interestingly, if p53 is functionally present, Akt is downregulated and carcinoma cells undergo apoptosis; this effect is also dependent upon α6β4 in these cells. In contrast to carcinomas, tumor cell survival depends on the formation of HDs and the activation of NF-κB. VEGFR, VEGF receptor.
FIG. 5.
FIG. 5.
In vitro keratinocyte mitosis. Laminin-5 ligation or MAb cross-linking of β4 (in lipid rafts) results in the activation and recruitment of Shc to tyrosine 1526 on β4. The data suggest that this event is sufficient to activate the classical MAP kinase cell cycle progression pathway. Importantly, the activated EGF receptor (EGFR) competes with tyrosine phosphorylated β4 for Shc binding and can independently induce mitosis. PTP, protein tyrosine phosphatase.
See this image and copyright information in PMC

References

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