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JCS ePress online publication date 16 Sep 2003
doi: 10.1242/jcs.00760

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Research Article

The association of the tetraspanin D6.1A with the {alpha}6{beta}4 integrin supports cell motility and liver metastasis formation


Mikael Herlevsen, Dirk-Steffen Schmidt, Kaoru Miyazaki, and Margot Zöller*
* Author for correspondence (e-mail: m.zoeller{at}dkfz.de)

The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the {alpha}6{beta}4 integrin.

An antibody-defined molecule was identified by mass spectrometry and cloning as {alpha}6{beta}4 integrin. Transfection-induced expression of {alpha}6{beta}4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express {alpha}6{beta}4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between {alpha}6{beta}4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of {alpha}6{beta}4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, {alpha}6{beta}4 changes from an adhesion-supporting towards a migration-supporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of {alpha}6{beta}4 in tumor progression.
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