Cytokine and growth factor receptors in the nucleus: What's up with that?

Signaling via cell surface receptors that are anchored by a single transmembrane domain is a well-established paradigm. Ligand binding to the extracellular domain of the receptor facilitates receptor dimerization, which juxtaposes the intracellular domains, typically activating intrinsic or associated kinases. Two large families of tyrosine kinase activating receptors have been particularly well characterized: the receptor-type protein tyrosine kinases and the receptors for the a-helical cytokines, which activate non-covalently bound JAK family tyrosine kinases. Despite the well-established function of these receptors at the cell surface, both intact and cleaved receptors belonging to these families have been repeatedly detected in the nucleus. Furthermore, there is evidence that some of these receptors or receptor fragments function directly in modulating gene transcription. In this essay, I examine how close we are to demonstrating that direct translocation of receptors, or receptor fragments, from the cell surface to the nucleus is a physiologically relevant means of intracellular signaling that can supplant or complement canonical signaling cascades. J. Cell. Biochem. (c) 2005 Wiley-Liss, Inc.