| Abstract | There are many situations in which cells respond to extracellular ligands whose receptors lack intrinsic or constitutively-associated catalytic functions. Well-studied examples include the antigen receptors on B and T lymphocytes and antibody receptors on myeloid cells. Less studied examples include lipoprotein receptors that are activated by Reelin, a secreted molecule important for brain development, Ephrins, which are activated by Eph receptors on other cells, and C-type lectins. All these receptors have intracellular regions containing phosphorylation sites for Src family kinases (SFKs) that become phosphorylated when the receptors are activated by dimerization/oligomerization by ligand. Current models to explain signal regulation generally either invoke weak prior association of the receptors with SFKs, conformation changes in the receptor intracellular receptor regions that expose SFK binding sites, movement of clustered receptors to membrane domains with altered lipid composition, or various SFK-regulating enzymes. We use two known properties of SFKs - their ability to trans-activate by intermolecular autophosphorylation and the ability of active SFKs to bind to phosphorylated receptors - combined with rate constants and concentrations gleaned from the literature - to explain how transmembrane signaling can occur. No changes in receptor conformation and no other enzymes apart from a constitutive phosphatase are required. This core signal transduction mechanism may be fine-tuned by other molecules within the cell. |
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