Question

What mechanisms have we encountered that ensure that a signal initiated by a growth factor receptor can be greatly amplified as the signal is transduced down a signaling cascade in the cytoplasm? Conversely, what signaling cascade(s) strongly limit the possible amplification of a signal initiated at the cell surface?

Answer 1

Growth factor receptor is a RTK (Receptor tyrosine kinase) type receptor. Growth factor receptor consist of an extracellular domain which binds to the ligand, single transmembrane domain and a cytosolic domain which has protein tyrosine kinase activity. Most RTKs are monomeric. When ligand binds to the receptor , it results in the dimerization of the receptor. Ligand binding also leads to the activation of the intrensic protein- tyrosine kinase activity of the receptor anf autophosphorylation of the tyrosine residues in the cytosolic domain.

The cytosolic adaptor protein GRB2 binds to a specific phosphotyrosine on an activted ligand bound receptor and to the cytosolic guanine exchange factor,SOS protein.

SOS promotes formation of active RasGTP. Activated Ras binds to the N-terminal domain of Raf (MAP kinase-kinase-kinase), a serine/threonine kinase

Raf directly phosphorylates MEK(MAP kinase-kinase) on two serine residues.

MEK phosphorylates and activates ERK(MAP kinase). MAP kinases are serine/threonine kinases. MAP kinase phosphorylates many different proteins, including nuclear transcription factors, that mediate cellular responses.Phosphatases are present which results in the dephosphorylation in order to turn off the proliferting. signal. Another way is by removing the ligand from the receptor. Some antibodies are also used which binds to the receptor and prevents the binding of ligand.Some tyrosine based drugs also inhibits the cascading effects.