Two alternative mechanisms of receptor associated tyrosine kinase action
The first predicted that a receptor-associated tyrosine kinase would phosphorylate a series of target protein in the cytoplasm.
The second predicted phosphorylation of the cytoplasmic tail of a receptor affected the physical location of downstream signaling partners.
Recall -The EGF receptor has src homology
The v-src encoded oncoprotein
This was the first cellular oncoprotein to be studied
Mammalian cells transformed by the v-src oncogene
exhibit a radically altered shape
pump in glucose from the surrounding medium
grow in an anchorage-independent fashion
lose contact inhibition, and to form tumors.
How did Src affect a wide variety of cellular targets ????
Src was itself a phosphoprotein
It also carried phosphate groups attached covalently to one or more of its amino acid side chains.
This indicated that Src served as a substrate for phosphorylation by a protein kinase
either phosphorylating itself (autophosphorylation) or serving as the substrate of yet another kinase.
The detailed structure of Src helped understand signalling
SH2 domains are common protein domains
There are over 100 distinct SH2 domains each carried by different proteins
The second prediction is the most relevant:
Phosphorylation of the cytoplasmic tail of a receptor affected the physical location of downstream signaling partners.
SH2 groups explain how growth factor receptors activate Ras and acquire signaling specificity
GF-- TKR-- Grb2
Grb2 contains
an SH2 domain that binds to a phospho-tyrosine located on the tail of a receptor
-two SH3 domains that bind to proline-rich domains of Sos
GF-- TKR-- Grb2-- Sos-- Ras-- ??
Activated Ras - the effector loop
4 окт 2024
