The EGF receptor functions as a tyrosine kinase (TK)
EGF was found to have mitogenic effects when applied to a variety of epithelial cell types. EGF was able to bind to the surfaces of the cells whose growth it stimulated;
other cells to which EGF was unable to bind were unresponsive to its mitogenic effects.
An EGF receptor protein can specifically recognize EGF bind to it, and inform the cell interior
The EGF receptor
The cytoplasmic domain revealed a clear sequence similarity with the already-known sequence of the Src protein
Signal activated EGF leads to
the Src-like kinase in its cytoplasmic domain becoming activated
to phosphorylate tyrosines on certain cytoplasmic proteins thereby causes a cell to proliferate.
There are many receptor tyrosine kinases
Subsequent sequencing efforts revealed overall sequence similarities among a variety of tyrosine kinases, many of which can function as oncoproteins.
Truncated versions of the EGF receptor are found in a number of human tumor cell types.
A variety of growth factor receptors that are configured much like the EGF receptor have been found in human tumors to be overexpressed or synthesized in a structurally altered form
Autocrine signaling loops
Some human cancers produce as many as three distinct growth factors
Eg tumor growth factor-a, TGF-a
stem cell factor; or SCF;
insulin-like growth factor; or IGF
At the same time express the receptors for these three ligands, thereby establishing three autocrine signaling loops simultaneously.
In normal tissues,
the proliferation of individual cells almost always depends on signals received from other cells
Growth Factor activated receptors tyrosine kinase signal to ras
“Ras” carry covalently attached lipid tails, composed of farnesyl, palmitoyl, and is anchored to cytoplasmic membranes
the Ras molecule seemed to behave like a light switch that automatically turns itself off after a certain predetermined time.
Ras was found
to bind a GDP molecule when in its quiescent, inactive state
to jettison its bound GDP after receiving some stimulatory signal from upstream in a signaling cascade
to acquire a GTP molecule in place of the recently evicted GDP
to shift into an activated, signal-emitting configuration while binding this GTP
to cleave this GTP after a short period by using its own intrinsic GTPase function
Signalling to “Ras”
Mitogenic signals, transduced in some way by tyrosine kinase receptors, activated a guanine nucleotide exchange factor (GEF) for Ras.
Ras receives signals from upstream in a signalling cascade subsequently passes these signals on to a downstream targets
How does “Ras” signal?
Ras can operate as an oncoprotein:
Typically mutations strike either the 12th or the 61st codon of the reading frame of the ras gene
Rather than sending out short, carefully rationed pulses of growth-stimulating signals,
the oncoprotein emits these signals for a long, indefinite period of time. Thereby flooding the cell with these signals
Why do point mutations Activate oncogenes
Large-scale alterations of the ras proto-oncogenes,
such as deletions, are clearly not productive for cancer,
they result in the elimination of Ras protein function
The vast majority of point mutations striking ras protooncogenes
yield mutant Ras proteins that have lost rather than gained the ability to emit growth-stimulatory signals.
Only when the signal-emitting powers of Ras are left intact and its GTPase negative-feedback mechanism is inactivated does the Ras protein gain increased power to drive cell proliferation and transform the cell.
Point mutations in the GTPase domain keep ras active