The neuregulins comprise a subfamily of at least four epidermal growth factor (EGF)-like growth factors that influence a variety of cellular events, including proliferation, differentiation, migration, survival, and fate. The most thoroughly examined neuregulin, neu differentiation factor NDF (AKA:neuregulin-1; NRG1; also heregulin, glial growth factor, or acetylcholine receptor-inducing activity), has been shown to play essential roles in the development of cardiac and neural tissues and also has been shown to play a role in the postsynaptic development of the neuromuscular junction. The neuregulins bind to ErbB3 or ErbB4 and can activate the ErbB2 receptor through a heterodimerization mechanism not shown in this illustration. Heterodimers of ErbB3 and ErbB2, which has no direct ligand, are potent in causing cell transformation.Controlled levels of signaling through ErbB and other growth factor receptors are maintained by keeping a relatively limited amount of receptors at the cell surface. Receptor overexpression can lead to disease states such as the genesis or progression of tumors. Hence, mechanisms must exist for localizing and maintaining a precise concentration of growth factor receptors at the site of signal reception. ErbB2, ErbB3, and ErbB4 are somewhat unique among studied receptor tyrosine kinases in that they exhibit impaired ligand-induced internalization, down-regulation, and degredation. Infact the rate of degredation is dependent on factors that appear to act independent of ligand binding. Nrdp-1 (Neuroregulin receptor degradation protein-1) is one such protein. Ndrp-1 is an E3 ubiqitin ligase that tags ErbB3 for degredation in non-lysosomal compartments. The cycling of ErbB1 is similar to that of EGF receptor and is included for contrast. The EGFR cycling is illustrated on the CBL Pathway.
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REFERENCES: Diamonti AJ, Guy PM, Ivanof C, Wong K, Sweeney C, Carraway KL 3rd. An RBCC protein implicated in maintenance of steady-state neuregulin receptor levels. Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2866-71. Qiu XB, Goldberg AL. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14843-8 Waterman H, Alroy I, Strano S, Seger R, Yarden Y. The C-terminus of the kinase-defective neuregulin receptor ErbB-3 confers mitogenic superiority and dictates endocytic routing. EMBO J. 1999 Jun 15;18(12):3348-58. Waterman H, Sabanai I, Geiger B, Yarden Y. Alternative intracellular routing of ErbB receptors may determine signaling potency. J Biol Chem. 1998 May 29;273(22):13819-27. Waterman H, Yarden Y. Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases. FEBS Lett. 2001 Feb 16;490(3):142-52. Review.
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