Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

Abstract

Immunoreceptor tyrosine-based activation motifs (ITAMs) are involved in the transduction of signals necessary for activation, differentiation, and survival in hematopoietic cells. Several viruses have been shown to encode ITAM-containing transmembrane proteins. Although expression of these viral proteins has in some cases been shown to transform nonhematopoietic cells, a causal role for a functional ITAM in this process has not been elucidated. To examine the potential transforming properties of ITAM-containing proteins, a recombinant protein consisting of ITAM-containing cytoplasmic regions of the B-cell antigen receptor was expressed in immortalized murine mammary epithelial and fibroblast cells. Mammary epithelial cells expressing this construct exhibited depolarized morphology in three-dimensional cultures. This transformed phenotype was characterized by a loss of anchorage dependence and hallmarks of epithelial to mesenchymal transition. Fibroblasts expressing this ITAM construct also lost contact inhibition and anchorage dependence. The transformed phenotype seen in both cell types was abrogated upon tyrosine to phenylalanine substitutions of the ITAMs. Inhibition of Syk tyrosine kinase, which associates with the ITAM, also prevented cell transformation. Our results indicate that expression of a nonviral ITAM-containing protein is sufficient for cell transformation. Despite lacking intrinsic enzymatic activity, ITAM-containing proteins can function as potent oncoproteins by scaffolding downstream mediators.

CD19 is a major B cell receptor–independent activator of MYC-driven B-lymphomagenesis

“…Specifically, PAX5-dependent neoplastic growth could be reduced by overexpression of immunoreceptor tyrosine-based activation motif-specific (ITAM-specific) CD22 phosphatase or treatment with Syk inhibitors or mimicked by forced expression of the constitutively active ITAM construct (28). Subsequent data using transgenic mouse models validated the idea that MYC and BCR signaling pathways cooperate during B-lymphomagenesis (29).…”

C35 (C17orf37) is a novel tumor biomarker abundantly expressed in breast cancer

“…Membrane association, predicted phosphorylation sites, and the presence of an immunoreceptor tyrosine-based activation motif suggest the possibility that C35 participates in signal transduction cascades. Immunoreceptor tyrosine-based activation sequences alone, with proper membrane localization and functional phosphorylation sites, have recently been shown to be potent oncogenes when transfected into epithelial cell lines (34). The significance of these motifs within C35 and understanding protein function may define C35 ¶s role in tumorigenesis as well as illuminate development of targeted therapies and diagnostic methods involving this novel biomarker.…”

Migration and invasion enhancer 1 (MIEN1) is overexpressed in breast cancer and is a potential new therapeutic molecular target

“…MIEN1 is a membraneanchored protein that is highly expressed in more than 60% of breast cancers, and contains a canonical immunoreceptor tyrosine-based activation motif (ITAM) sequence and a thioredoxin-like fold. ITAM-containing proteins can contribute to mammary epithelial cell transformation, and are closely associated with epithelial-mesenchymal transition (Grande et al, 2006). Recently, a study by Li et al (2016) suggested that downregulation of MIEN1 by simvastatin inhibits the proliferation of colon cancer.…”