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MBC in Press, published online ahead of print August 15, 2007
Mol. Biol. Cell 10.1091/mbc.E06-08-0720

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Submitted on August 16, 2006
Revised on July 28, 2007
Accepted on August 7, 2007

Dual Role of {alpha}6{beta}4 Integrin in Epidermal Tumor Growth: Tumor-suppressive Versus Tumor-promoting Function

Karine Raymond,* Maaike Kreft,* Ji-Ying Song,{dagger} Hans Janssen,* and Arnoud Sonnenberg*

*Division of Cell Biology and {dagger}Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Monitoring Editor: Martin A. Schwartz

An increased expression of the integrin {alpha}6{beta}4 is correlated with a poor prognosis in patients with squamous cell carcinomas. However, little is known about the role of {alpha}6{beta}4 in the early stages of tumor development. We have isolated cells from mouse skin (mTICs) that are deficient in both p53 and Smad4 and carry conditional alleles of the {beta}4 gene (Itgb4). The mTICs display many features of multipotent epidermal stem cells and produce well-differentiated tumors after subcutaneous injection into nude mice. Deletion of Itgb4 led to enhanced tumor growth, indicating that {alpha}6{beta}4 mediates a tumor suppressive effect. Reconstitution experiments with {beta}4-chimeras showed that this effect is not dependent on ligation of {alpha}6{beta}4 to laminin-5, but on the recruitment by this integrin of the cytoskeletal linker protein plectin to the plasma membrane. Depletion of plectin, like that of {beta}4, led to increased tumor growth. In contrast, when mTICs had been further transformed with oncogenic Ras, {alpha}6{beta}4 stimulated tumor growth, as previously observed in human squamous neoplasms. Expression of different effector-loop mutants of RasV12 suggests that this effect depends on a strong activation of the Erk pathway. Together, these data show that depending on the mutations involved, {alpha}6{beta}4 can either mediate an adhesion-independent tumor-suppressive effect or act as a tumor promotor.

Address correspondence to: Arnoud Sonnenberg (a.sonnenberg{at}nki.nl)






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