Protooncogene (RET) Antibody – Mouse Monoclonal

Function: Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Ref.8 Ref.10

Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.

Enzyme regulation: Repressed by withaferin A (WA). Ref.11

Subunit structure: Phosphorylated form interacts with the PBT domain of DOK2, DOK4 and DOK5. The phosphorylated form interacts with PLCG1 and GRB7. Interacts (not phosphorylated) with PTK2/FAK1 (via FERM domain). Extracellular cell-membrane anchored RET cadherin fragments form complex in neurons with reduced trophic status, preferentially at the contact sites between somas. Interacts with AIP in the pituitary gland; this interaction prevents the formation of the AIP-survivin complex. Binds to ARTN. Interacts (inactive) with CBLC and CD2AP; dissociates upon activation by GDNF which increases CBLC:CD2AP interaction. Ref.6 Ref.7 Ref.8 Ref.9

Subcellular location: Cell membrane; Single-pass type I membrane protein. Endosome membrane; Single-pass type I membrane protein

By similarity.

Tissue specificity: Expressed in peripheral nerve cells, hematopoietic cells and podocytes. Ref.9

Post-translational modification: Autophosphorylated on C-terminal tyrosine residues upon ligand stimulation. Dephosphorylated by PTPRJ on Tyr-906, Tyr-1016 and Tyr-1063

By similarity. Ref.7 Ref.12Proteolytically cleaved by caspase-3. The soluble RET kinase fragment is able to induce cell death. The extracellular cell-membrane anchored RET cadherin fragment accelerates cell adhesion in sympathetic neurons

By similarity.

Disruption phenotype: Exclusive loss in nociceptors results in a reduction in nociceptor number and size with a reduced epidermal innervation, but increased sensitivity to cold and increased formalin-induced pain. Ref.10

Miscellaneous: Treatment with withaferin A (WA) leads tumor regression in medullary thyroid carcinomas (MTC).

Sequence similarities: Belongs to the protein kinase superfamily. Tyr protein kinase family.Contains 1 cadherin domain.Contains 1 protein kinase domain.