Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.).
Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
Pharmacol Rev. 2022 Jan;74(1):18-47. doi: 10.1124/pharmrev.121.000381.
ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and mutants in staging and treating human tumors.
ERBB4（HER4）是受体酪氨酸激酶 ERBB 家族的成员，该家族包括表皮生长因子受体（EGFR/ERBB1/HER1）、ERBB2（Neu/HER2）和 ERBB3（HER3）。EGFR 和 ERBB2 是癌蛋白，是多种实体瘤治疗干预的有效靶点。相比之下，ERBB4 在人类恶性肿瘤中的作用尚不清楚。因此，我们在这里回顾了有关 ERBB4 在人类恶性肿瘤中功能的文献。我们回顾了 ERBB4 信号转导的机制，重点讨论了信号转导特异性的机制。在这种信号转导特异性的背景下，我们讨论了 ERBB4 似乎作为肿瘤抑制蛋白和癌蛋白发挥作用的假说。接下来，我们回顾了描述 ERBB4 在膀胱癌、肝癌、前列腺癌、脑癌、结肠癌、胃癌、肺癌、骨癌、卵巢癌、甲状腺癌、造血组织癌、胰腺癌、乳腺癌、皮肤癌、头颈部癌中的作用的文献。在可能的情况下，我们讨论了 ERBB4 突变体在这些肿瘤中作为生物标志物的可能性。最后，我们讨论了 ERBB4 突变体在人类肿瘤分期中的潜在作用以及 ERBB4 功能如何决定人类肿瘤的治疗。意义陈述：本文在 ERBB4 同源二聚体作为肿瘤抑制因子，而 ERBB4-EGFR 或 ERBB4-ERBB2 异源二聚体作为癌基因的作用的机制模型的背景下，综述了 ERBB4 的功能。因此，本综述为临床医生和科学家提供了一个机制框架，以考虑 ERBB4 和突变体在分期和治疗人类肿瘤中的作用。
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