Nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants, enhancing their activation and DNA synthesis

Abstract

Nectin-4 cell adhesion molecule and ErbB2 tyrosine kinase receptor are upregulated in many cancers, including breast cancer, and promote cancer cell proliferation and metastasis. Using human breast cancer cell lines T47D and SUM190-PT, in which both nectin-4 and ErbB2 were upregulated, we showed here that nectin-4 cis-interacted with ErB2 and enhanced its dimerization and activation, followed by the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. The third immunoglobulin-like domain of nectin-4 cis-interacted with domain IV of ErbB2. This region differs from the trastuzumab-interacting region but is included in the trastuzumab-resistant splice variants of ErbB2, p95-ErbB2 and ErbB2ΔEx16. Nectin-4 also cis-interacted with these trastuzumab-resistant splice variants and enhanced the activation of the phosphoinositide 3-kinase-AKT signalling pathway for DNA synthesis. In addition, nectin-4 enhanced the activation of the p95-ErbB2-induced JAK-STAT3 signalling pathway, but not the ErbB2- or ErbB2ΔEx16-induced JAK-STAT3 signalling pathway. These results indicate that nectin-4 cis-interacts with ErbB2 and its trastuzumab-resistant splice variants and enhances the activation of these receptors and downstream signalling pathways in a novel mechanism.

Nectin-4 and p95-ErbB2 cooperatively regulate Hippo signaling-dependent SOX2 gene expression, enhancing anchorage-independent T47D cell proliferation

“…The SOX2 gene expression is induced by many signaling pathways including the PI3K-AKT signaling 45 – 49 . Detailed studies revealed here that nectin-4 and any one of p95-ErbB2, ErbB2, or ErbB2∆Ex16 cooperatively activated the PI3K-AKT signaling to similar extents 33 , but that only the combination of nectin-4 and p95-ErbB2, but not that of nectin-4 and either ErbB2 or ErbB2∆Ex16, cooperatively activated the Hippo signaling to regulate the SOX2 gene expression. In this signaling pathway, MST1/2 phosphorylates and activates LATS1/2, which in turn phosphorylates YAP, keeping the phosphorylated YAP in the cytoplasm, thus inhibiting its activity 50 .…”

“…We further showed that nectin-4 also cis -interacts with the trastuzumab-resistant splice variants of ErbB2, p95-ErbB2 and ErbB2∆Ex16, activating the PI3K-AKT signaling and enhancing DNA synthesis 33 . In addition, nectin-4 activates the p95-ErbB2-induced JAK-STAT signaling, but not the ErbB2- or ErbB2∆Ex16-induced JAK-STAT signaling 33 .…”

“…Nectin-4 belongs to the nectin and nectin-like molecule (Necl) superfamily that comprises two families, the nectin family with four members (nectin-1, -2, -3, and -4) and the Necl family with five members (Necl-1, -2, -3, -4, and -5) 26 – 28 . Nectins and Necls homophilicaly or heterophilicaly trans -interact with each other and further cis -interact with many cell surface membrane receptors, including growth factor receptors, hormone receptors, and integrins, eventually regulating various cell functions, including cell proliferation, survival, migration, and differentiation, in addition to cell adhesion 29 – 33 .…”

“…We previously showed using human breast cancer T47D and SUM190-PT cells that nectin-4 cis -interacts with ErbB2 and enhances its homo-dimerization and activation in a novel mechanism, activating the PI3K-AKT signaling and enhancing DNA synthesis 33 . We further showed that nectin-4 also cis -interacts with the trastuzumab-resistant splice variants of ErbB2, p95-ErbB2 and ErbB2∆Ex16, activating the PI3K-AKT signaling and enhancing DNA synthesis 33 . In addition, nectin-4 activates the p95-ErbB2-induced JAK-STAT signaling, but not the ErbB2- or ErbB2∆Ex16-induced JAK-STAT signaling 33 .…”

NECTIN4 Expression in Extramammary Paget’s Disease: Implication of a New Therapeutic Target

“…Nectin cell adhesion molecule 4 is normally expressed in the epithelium of the bladder, epidermis of the skin, salivary glands (ducts), and mammary glands [16,22]. Interestingly, NECTIN4 is overexpressed in some epithelial cancers, and its overexpression is correlated with tumor progression and patient outcome [16,22,23,26]. However, the detailed expression of NECTIN4 in human skin and its role in skin tumors have not been examined.…”