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ROS1 Signaling Pathway

The c-ros oncogene 1 (ROS1) is a receptor tyrosine kinase with structural similarity to anaplastic lymphoma kinase (ALK) protein. It was discovered in the 1980s as the oncogene product of the chicken sarcoma RNA UR2 (University of Rochester) tumor virus. The receptor is expressed during development, but little is expressed in adults and its physiological function is unknown.

An Overview of ROS1

The human ROS1 gene is located on chromosome 6 and encodes a 2,347 amino acid residues consisting of an extracellular ligand-binding domain composed of nine repeated fibronectin-like motifs, a short transmembrane domain, and an intracellular TK domain. Although very little is known of the extracellular domain function of this orphan receptor, the structural combination of ROS1 suggests its ability to directly couple extracellular adhesion-mediated events to tyrosine phosphorylation-based intracellular signaling.

To date, seven distinct ROS1 gene fusions have been identified in solid tumors including fused in glioblastoma (FIG)-ROS1, CD74-ROS1, solute carrier family 34 (sodium phosphate), member 2 (SLC34A2)-ROS1, tropomyosin 3 (TPM3)-ROS1, syndecan 4 (SDC4)-ROS1, ezrin (EZR)-ROS1, leucine-rich repeats, and immunoglobulin-like domains 3 (LRIG3-ROS1) all of which encoded the same cytoplasmic portion of ROS1 TK domain. The break point of ROS1 with EZR is exon 34, TPM3, FIG, and LRIG3 is exon 35 whereas for CD74, SDC4, and SLC34A2 are exons 32 and 34. (Table1). All of the breakpoints in ROS1 allow the resulting fusion to retain the ROS1 kinase domain whereas with SDC4-ROS1, the ROS1 transmembrane domain is also retained.

Table 1. ROS1 Fusion Variants in Cancer. (Chin, L. P; et al. 2012)

ROS1 Fusion Variants in Cancer

The Process of ROS1 Signaling Pathways

ROS1 engages multiple signaling pathways to exert its transformation activity. phospholipase C, gamma (PLCγ), mitogen-activated protein kinase (MAPK), insulin receptor substrate 1 (IRS1 signaling molecule to PI3K), vav 3 guanine nucleotide exchange factor 1 (VAV3), signal transducers and activators of transcription-3 (STATS), cytoskeleton and cell-to-cell interaction (β-integrin, tensin, α-, β-, δ-catenin, N-catenin) proteins can interact with ROS1, and phospohorylation of these proteins by ROS1 can lead to activation of the respective oncogenic pathways.

Dysregulated ROS1 may occur as a result of ROS1 gene fusion, overexpression, or mutations. Aberrant ROS1 kinase activity leads to activated downstream signaling of several oncogenic pathways including the phosphoinositide-3 kinase/v-akt murine thymoma viral oncogene homolog 1 (AKT)/mechanistic target of rapamycin (serine/threonine kinase) (mTOR), signal transducers and activators of transcription-3, RAS-MAPK/ERK, VAV3 and Src-homology 2 domain-containing phosphatase (SHP)-1 and SHP-2 pathways. ROS autophosphorylation sites are docking sites for the tyrosine phosphatases SHP-1 and SHP, Src-homology 2 domain-containing phosphatase.

With the activation of ALK fusion proteins, the downstream signaling pathways are similar to ROS1 RTK activation with the involvement of the RAS-RAF-MEK-MAPK, Janus kinase 3-signal transducers and activators of transcription-3, and phosphoinositide-3 kinase/Akt pathways, which control cell proliferation, survival, and cell cycling. However, unlike the echinoderm microtubule-associated protein-like 4 (EML4)-ALK gene fusion in which the coiled-coil domain within echinoderm microtubule-associated protein-like 4 mediates the constitutive dimerization resulting in aberrant constitutive activity, protein dimerization domains have not been described in ROS1 fusion receptor tyrosine kinases.

The Studies for ROS1 Signaling Pathway

Owing to the lack of a known activating ligand, there have been few studies on the ROS1 signal transduction pathways. The generation of chimeric receptors containing the extracellular domain of the epidermal growth factor or nerve growth factor receptors with the ROS1 protein kinase domain has been employed to study signaling pathways. These studies have coupled the chimeric receptors with AKT, the phosphatidyl inositol 3 kinase, STAT3, Vav3, SHP-1/2, and the mitogen-activated protein kinase ERK1/2.

References:

1. Chin, L. P; et al. Targeting ROS1 with Anaplastic Lymphoma Kinase Inhibitors. Journal of Thoracic Oncology. 2012, 7: 1625-1630.
2. Shih, C. H; et al. EZH2-mediated upregulation of ROS1 oncogene promotes oral cancer metastasis. 2017, 36: 6542-6554.

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