Somatic Mutations of ErbB4

Abstract

Cancer drugs targeting ErbB receptors, such as epidermal growth factor receptor and ErbB2, are currently in clinical use. However, the role of ErbB4 as a potential cancer drug target has remained controversial. Recently, somatic mutations altering the coding region of ErbB4 were described in patients with breast, gastric, colorectal, or non-small cell lung cancer, but the functional significance of these mutations is unknown. Here we demonstrate that 2 of 10 of the cancer-associated mutations of ErbB4 lead to loss of ErbB4 kinase activity due to disruption of functionally important structural features. Interestingly, the kinase-dead ErbB4 mutants were as efficient as wild-type ErbB4 in forming a heterodimeric neuregulin receptor with ErbB2 and promoting phosphorylation of Erk1/2 and Akt in an ErbB2 kinase-dependent manner. However, the mutant ErbB4 receptors failed to phosphorylate STAT5 and suppressed differentiation of MDA-MB-468 mammary carcinoma cells. These findings suggest that the somatic ErbB4 mutations have functional consequences and lead to selective changes in ErbB4 signaling.The ErbB/epidermal growth factor receptor (EGFR) 3 /HER receptor-tyrosine kinase subfamily includes EGFR, ErbB2, ErbB3, and ErbB4. ErbB receptors bind several EGF-like growth factors including the neuregulins (NRG). Ligand-induced extracellular homo-or heterodimerization of ErbB receptors is followed by autophosphorylation at intracellular tyrosine residues by juxtaposed tyrosine kinase domains. The phosphorylated tyrosines in the cytoplasmic receptor tail serve as binding sites for various intracellular signal transduction molecules that mediate the cellular responses to ErbB stimulation (1, 2).Recent crystallographic and biochemical analyses have indicated that intracellular tyrosine kinases of EGFR and ErbB4 are activated allosterically in an asymmetrical fashion (3, 4). In the activated dimer the C-terminal lobe of one kinase domain contacts with the N-terminal lobe of another kinase domain, thereby breaking its intrinsic autoinhibited conformation and facilitating catalysis (3, 4). Activation mechanisms of protein kinases have shared features, and the relative spatial orientation of certain residues that are highly conserved within the eukaryotic protein kinome is essential for successful catalysis (5). These include residues that participate in nucleotide binding and transfer of the ␥-phosphate group of adenosine triphosphate (ATP) to the hydroxyl oxygen atom of a substrate. Conserved regulatory elements of protein kinases include the activation (A)-loop, ␣C-helix, phosphate binding (P)-loop, and catalytic (C)-loop. The A-loop is involved in stabilizing the inactive conformation, whereas the ␣C-helix, located in the N-terminal lobe, mediates conformational changes within the catalytic center that activate the kinase. The aspartate-phenylalanine-glycine (DFG) motif at the base of the A-loop and the P-loop participate in binding and coordination of ATP, whereas the C-loop contains the catalytic aspartate residue (Asp-843 in ...

Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing

“…When bound by ligands like neuregulin, ERBB4 activates numerous downstream pathways, including Ras/MAPK/ERK and PI3K/AKT signaling (via mTOR), to regulate both normal cellular processes and cancer development and progression [23–25]. We identified five ERBB4 mutations, three of which (p.P6619S, p.P981S and p.P996S) were annotated in Cosmic (http://cancer.sanger.ac.uk/cosmic/gene/; accessed 09202016) (Supplementary Table 2) and in four samples.…”

Whole-Exome Sequencing of Salivary Gland Mucoepidermoid Carcinoma

“…MAP3K9 (26) and ERBB4 (27) encode for protein kinases that have been frequently implicated in human cancers and may be potential therapeutic targets. IRAK1 encodes interleukin-1 (IL-1) receptor-associated kinase 1, which is a serine/threonine protein kinase that associates with the IL-1 receptor upon stimulation.…”

ERBB4 Promoter Polymorphism Is Associated with Poor Distant Disease-Free Survival in High-Risk Early Breast Cancer

“…The other mutation, G802dup, has previously been reported in non-small cell lung cancer [15]. Both mutations have been shown to be functional and promote cancer cell/tumor growth in vitro [16], [17], suggesting the presence of rare but potentially oncogenic ERBB4 mutations in breast cancer. Although the observed ERBB4 mutation frequency (0.2%) is low, it corresponds to the frequency of ERBB2 kinase domain mutations (0.5%) in the same patient cohort [24].…”

“…The frequency of the analyzed ERBB4 kinase domain mutations was low (0.2%). However, both somatic mutations had previously been shown to be functional and promote cancer cell growth in vitro [16], [17], suggesting a presence of rare but oncogenic ERBB4 mutations in breast cancer.…”