The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein

Abstract

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 ERBB4 mutants in staging and treating human tumors.

Graphical abstract

Fig. 1

Organization of ERBB receptors. The amino-terminal extracellular region consists of four subdomains (I–IV) responsible for ligand binding and receptor dimerization. Note the dimerization motifs in subdomains II and IV that stabilize the intramolecular interactions characteristic of the closed conformation and enable the intermolecular interactions necessary for dimerization of two receptor molecules that exist in the open conformation. A hydrophobic transmembrane domain lies between the extracellular region and the cytoplasmic tyrosine kinase domain. This kinase domain can be divided into amino-terminal (N) and carboxyl-terminal (C) lobes. Several sites of tyrosine phosphorylation (Y) reside at the carboxyl terminus of these receptors. Finally, note that ligand binding stabilizes a receptor molecule in the open conformation.

Fig. 2

Ligand-induced ERBB receptor signaling. Eleven members of the EGF family of peptide growth factors bind to EGFR, ERBB3, and ERBB4. Some EGF family members bind to multiple ERBB family receptors, but no EGF family member binds to ERBB2. The binding of an EGF family hormone to a receptor stabilizes the extracellular domain of the receptor in an open conformation that enables receptor dimerization. ERBB receptors can either homodimerize or heterodimerize. The symmetrical dimerization of the extracellular region of two ERBB receptors causes asymmetric dimerization of the cytoplasmic regions. This asymmetric dimerization enables the kinase domain of one monomer to allosterically stimulate the kinase activity of the other monomer. This results in transphosphorylation of one monomer by the other on tyrosine residues.

Fig. 3

The cytoplasmic domain of ERBB4 possesses several candidate and validated sites of tyrosine phosphorylation. These sites of ERBB4 tyrosine phosphorylation are depicted along with candidate and validated effector proteins that directly or indirectly interact with these phosphorylation sites. The cytoplasmic domain is not depicted to scale.

Fig. 4

Additional motifs and effectors that modulate and mediate ERBB4 signaling. The cytoplasmic region of ERBB4 is depicted along with the differences in the amino-acid sequence of the four ERBB4 splicing isoforms. Sites of ERBB4 functional motifs are indicated, along with the particular downstream signaling effectors that bind to these sites. The cytoplasmic region is not depicted to scale.

Fig. 5

Interactions of the 4ICD with partner proteins. The intracellular region of ERBB4 (4ICD) is depicted, along with the various partner proteins that are known to interact with the 4ICD in the nucleus and the cytoplasm. The biologic effect of each 4ICD complex is listed. The figure is not drawn to scale.

Fig. 6

The 4ICD regulates events in the mitochondria. The 4ICD translocates from the membrane to the outer mitochondrial membrane. Indirect and direct interactions of the 4ICD with BAK results in cytochrome C efflux and apoptotic cell death. The figure is not drawn to scale.

Fig. 7

A proposed role for ERBB4 in human malignancies.