Neuregulin 1–activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration

Abstract

The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that when phosphorylated, ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that activates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the tumor-suppressor Hippo pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did preventing ERBB4 cleavage by treating cells with the pan-EGFR inhibitors lapatinib or erlotinib. A PPxY motif in the ERBB4 ICD enabled its interaction with WW domains in YAP, similar to the mode of interaction between YAP and the kinase LATS1, which inhibits the transcriptional activity of YAP. The ERBB4 ICD coimmunoprecipitated with YAP and TEAD1, a YAP coactivator, suggesting that the ERBB4 ICD may functionally interact with YAP and TEAD to promote transcriptional activity. NRG1 stimulated YAP activity to an extent comparable to that of EGF or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling may underlie the aggressive behavior of tumor cells.

Phosphorylation of Tyr188 in the WW domain of YAP1 plays an essential role in YAP1-induced cellular transformation

“…Although Src, Yes, ErbB4 and EGFR are candidate kinases for Y188 phosphorylation of YAP1, 12,30,41,42 we decided to search for the potential tyrosine kinases responsible for the YAP1-Y188 phosphorylation in an unbiased way, via in silico analysis using the GPS 2.0 (Group-based Prediction System, version 2.0) software (http://gps.biocuckoo.org/). 43 We identified several intriguing candidates including Tec, JakA, PDGFR and Met kinases (Fig.…”

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“…In addition, YAP and TAZ expression is elevated in advanced breast cancer and inversely correlates with metastasis-free survival [16]. Nuclear translocation of YAP and TAZ can be driven by the Epidermal Growth Factor Receptor family member ErbB-4 and/or EGFR-dependent activation of the MAP Kinase pathway [17,19,20]. In fact, autocrine loops between the EGFR pathway and YAP activation have been identified in ovarian cancer and breast epithelium [21,22].…”

“…This transcription factor family is a known modulator of epithelial differentiation [9][10][11][12] and their activity may drive stem-cell like phenotypes [13][14][15]. Nuclear translocation of YAP and TAZ can also promote breast cancer stem Priority Research Paper cell properties including self-renewal, migration, and tumor-initiating abilities [16][17][18]. In addition, YAP and TAZ expression is elevated in advanced breast cancer and inversely correlates with metastasis-free survival [16].…”

Analysis of Copy Number Loss of the ErbB4 Receptor Tyrosine Kinase in Glioblastoma

“…With regards to signaling and cancer, ERBB4 activates several of the same downstream proteins as EGFR-such as CBL, STAT5, and SHC 2 but also strongly activates PI3K signaling 2,3 . Its overexpression has been associated with melanoma, medulloblastoma, and breast cancer progression 4,8 . However, it remains unclear what role, if any, ERBB4 plays in the progression of gliomas.…”

“…ERBB4 binds several ligands including betacellulin, HB-EGF, and epiregulin that also bind to EGFR 2 but additionally other ligands such as neuregulin 1-4 (NRG1, NRG2, NRG3, and NRG4) 7 . ERBB4 is essential to cardiac, mammary, and neural development 2,8 and is implicated in schizophrenia 9 . With regards to signaling and cancer, ERBB4 activates several of the same downstream proteins as EGFR-such as CBL, STAT5, and SHC 2 but also strongly activates PI3K signaling 2,3 .…”