IRE1[alpha] is a transmembrane protein which self-activates via homo-dimerization and transphosphorylation
during the UPR.
Since sensor kinase and response regulator communicate via transphosphorylation
reaction, this reaction requires the formation of precise but transient complex between the phosphorylation domain of SK and phospho-acceptor domain of RR (50).
Insulin resistance implies changes upon insulin signaling, mainly in a transphosphorylation
reaction that activates the insulin receptor substrate (IRS), an intrinsic kinase that activates the phosphatidylinositol 3-kinase- (PI3K-) AKT/protein kinase B (PKB) pathway to modulate most metabolic functions of insulin, such as glucose transport by GLUT-4 in adipocytes and myocytes.
Triggered by the dimerization of receptors, the transphosphorylation
and activation of FGFRs initiate signaling via multiple downstream intracellular pathways .
Afatinib (Giotrif) is an irreversible pan-EGFR family blocker , which inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation
within their dimerization and inhibition of critical steps in the signal transduction of all EGFR family members.
In fact, tofacitinib as well as SOCS1/3 impede auto- and transphosphorylation
of JAK, with the first blocking ATP binding site of JAK1-2-3 and competing with ATP , and SOCS1/ 3 by interacting with the -GQM-amino acidic residues of JAK, determinant for its binding to substrates .
The binding of insulin to the alpha subunit of the IR (Figure 1) promotes transphosphorylation
of tyrosine residues (Tyr) in the beta subunit of the receptor (located in the intracellular region), which mediates the phosphorylation of IRSs (13,32).
In vitro studies showed that [p185.sup.neu] autophosphorylation and transphosphorylation
were inhibited by curcumin.
Ligand binding leads to a functional receptor core of these two components, inducing the transphosphorylation
of receptor-associated kinases JAK1 and JAK3 and activation of STAT5.
Insulin binding to the insulin receptor (InsR) promotes a conformational change in the receptor which leads to the transphosphorylation
in tyrosine residues of its cytoplasmic p subunits .
The IFNs bind to a heterodimeric transmembrane receptor which results in the recruitment and activation of tyrosine kinases, JAK1 and TYK2, through auto- and transphosphorylation
. This process drives the recruitment and subsequent phosphorylation of the cytoplasmic transcription factors, STAT1 and STAT2, which translocate to the nucleus and associate with IRF9 to activate IFN genes.
The HER2 protein is analogous to other receptor tyrosine kinases: it is expressed at the cell surface; it exists there in homodimeric form, as well as in heterodimers with other ErbB family members; and it possesses intracellular domains capable of transphosphorylation
and interaction with downstream effectors.