Wilson Kristy J, Gilmore Jennifer L, Foley John, Lemmon Mark A, Riese David J
Purdue University School of Pharmacy and Purdue Cancer Research Center, West Lafayette, IN 47907-2064, USA.
Pharmacol Ther. 2009 Apr;122(1):1-8. doi: 10.1016/j.pharmthera.2008.11.008. Epub 2008 Dec 16.
Breast, prostate, pancreatic, colorectal, lung, and head and neck cancers exploit deregulated signaling by ErbB family receptors and their ligands, EGF family peptide growth factors. EGF family members that bind the same receptor are able to stimulate divergent biological responses both in cell culture and in vivo. This is analogous to the functional selectivity exhibited by ligands for G-protein coupled receptors. Here we review this literature and propose that this functional selectivity of EGF family members is due to distinctions in the conformation of the liganded receptor and subsequent differences in the sites of receptor tyrosine phosphorylation and receptor coupling to signaling effectors. We also discuss the roles of divergent ligand activity in establishing and maintaining malignant phenotypes. Finally, we discuss the potential of mutant EGF family ligands as cancer chemotherapeutics targeted to ErbB receptors.
乳腺癌、前列腺癌、胰腺癌、结直肠癌、肺癌以及头颈癌会利用表皮生长因子受体（ErbB）家族受体及其配体（表皮生长因子[EGF]家族肽生长因子）的信号传导失调。结合相同受体的表皮生长因子家族成员在细胞培养和体内均能够刺激不同的生物学反应。这类似于配体对G蛋白偶联受体所表现出的功能选择性。在此，我们回顾了这方面的文献，并提出表皮生长因子家族成员的这种功能选择性是由于配体结合型受体构象的差异以及随后受体酪氨酸磷酸化位点和受体与信号效应器偶联的差异所致。我们还讨论了不同配体活性在建立和维持恶性表型中的作用。最后，我们探讨了突变型表皮生长因子家族配体作为靶向表皮生长因子受体的癌症化疗药物的潜力。
