Wali Vikram B, Haskins Jonathan W, Gilmore-Hebert Maureen, Platt James T, Liu Zongzhi, Stern David F
Department of Pathology, Yale School of Medicine, New Haven, Connecticut
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Mol Cancer Res. 2014 Aug;12(8):1140-55. doi: 10.1158/1541-7786.MCR-13-0637. Epub 2014 May 14.
Associations of ErbB4 (ERBB4/HER4), the fourth member of the EGFR family, with cancer are variable, possibly as a result of structural diversity of this receptor. There are multiple structural isoforms of ERBB4 arising by alternative mRNA splicing, and a subset undergo proteolysis that releases membrane-anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription. To compare the differential and common signaling activities of full-length (FL) and soluble intracellular isoforms of ERBB4, four JM-a isoforms (FL and soluble intracellular domain (ICD) CYT-1 and CYT-2) were expressed in isogenic MCF10A cells and their biologic activities were analyzed. Both FL and ICD CYT-2 promoted cell proliferation and invasion, and CYT-1 suppressed cell growth. Transcriptional profiling revealed several new and underexplored ERBB4-regulated transcripts, including: proteases/protease inhibitors (MMP3 and SERPINE2), the YAP/Hippo pathway (CTGF, CYR61, and SPARC), the mevalonate/cholesterol pathway (HMGCR, HMGCS1, LDLR, and DHCR7), and cytokines (IL8, CCL20, and CXCL1). Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses ERBB4. Furthermore, ChIP-seq experiments identified ADAP1, APOE, SPARC, STMN1, and MXD1 as novel molecular targets of ERBB4. These findings clarify the diverse biologic activities of ERBB4 isoforms, and reveal new and divergent functions.
ErbB4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer.
表皮生长因子受体（EGFR）家族的第四个成员ErbB4（ERBB4/HER4）与癌症的关联是多变的，这可能是由于该受体的结构多样性所致。ERBB4通过可变的mRNA剪接产生多种结构异构体，其中一部分会经历蛋白水解，释放出膜锚定和可溶性异构体，这些异构体与转录因子和共调节因子结合以调节转录。为了比较ERBB4全长（FL）和可溶性细胞内异构体的差异和共同信号活性，在同基因MCF10A细胞中表达了四种JM-a异构体（FL和可溶性细胞内结构域（ICD）CYT-1和CYT-2），并分析了它们的生物学活性。FL和ICD CYT-2均促进细胞增殖和侵袭，而CYT-1则抑制细胞生长。转录谱分析揭示了一些新的和未充分研究的ERBB4调节转录本，包括：蛋白酶/蛋白酶抑制剂（MMP3和SERPINE2）、YAP/河马通路（CTGF、CYR61和SPARC）、甲羟戊酸/胆固醇通路（HMGCR、HMGCS1、LDLR和DHCR7）以及细胞因子（IL8、CCL20和CXCL1）。随后在通常表达ERBB4的腔面乳腺癌细胞系中验证了许多这些转录本。此外，染色质免疫沉淀测序（ChIP-seq）实验确定ADAP1、APOE、SPARC、STMN1和MXD1为ERBB4的新分子靶点。这些发现阐明了ERBB4异构体的多种生物学活性，并揭示了新的和不同的功能。
ErbB4作为河马通路和甲羟戊酸通路的调节因子，为正常乳腺上皮和癌症中的乳汁生成和合成代谢过程提供了新的见解。
