Intrinsic Signaling Functions of the β4 Integrin Intracellular Domain^*

Abstract

A key issue regarding the role of α6β4 in cancer biology is the mechanism by which this integrin exerts its profound effects on intracellular signaling, including growth factor-mediated signaling. One approach is to evaluate the intrinsic signaling capacity of the unique β4 intracellular domain in the absence of contributions from the α6 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 β4 transmembrane and intracellular domains. Expression of this chimeric receptor in β4-null cancer cells enabled us to assess the signaling potential of the β4 intracellular domain alone or in response to dimerization using brain-derived neurotrophic factor, the ligand for TrkB. Dimerization of the β4 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 α6β4. In contrast to α6β4 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 factor-mediated activation of Akt and Erk1/2, and growth factor-stimulated migration. Collectively, these data indicate that the β4 intracellular domain has some intrinsic signaling potential, but it cannot mimic the full signaling capacity of α6β4. These data also question the putative role of the β4 intracellular domain as an “adaptor” for growth factor receptor signaling.