Intrinsic signaling functions of the ß4 integrin intracellular domain

A key issue regarding the role of alpha 6 beta 4 in cancer biology is the mechanism by which this integrin exerts its profound effects on intracellular signaling, including growth factor-mediated signaling. Oneapproach is to evaluate the intrinsic signaling capacity of the unique beta 4 intracellular domain in the absence of contributions from the alpha 6 subunit and tetraspanins and to assess the ability of growth factor receptor signaling to cooperate with this domain. Here, we generated a chimeric receptor composed of the TrkB extracellular domain and the beta 4 transmembrane and intracellular domains. Expression of this chimeric receptor in beta 4-null cancer cells enabled us to assess the signaling potential of the beta 4 intracellular domain alone or in response to dimerization using brain-derived neurotrophic factor, the ligand for TrkB. Dimerization of the beta 4 intracellular domain results in the binding and activation of the tyrosine phosphatase SHP-2 and the activation of Src, events that also occur upon ligation of intact alpha 6 beta 4. In contrast to alpha 6 beta 4 signaling, however, dimerization of the chimeric receptor does not activate either Akt or Erk1/2. Growth factor stimulation induces tyrosine phosphorylation of the chimeric receptor but does not enhance its binding to SHP-2. The chimeric receptor is unable to amplify growth factormediated activation of Akt and Erk1/2, and growth factorstimulated migration. Collectively, these data indicate that the beta 4 intracellular domain has some intrinsic signaling potential, but it cannot mimic the full signaling capacity of alpha 6 beta 4. These data also question the putative role of the beta 4 intracellular domain as an adaptor for growth factor receptor signaling.