•ion-channel linked (opens an ion channel

•G-protein linked (trimeric and monomeric G proteins)

•enzyme-linked (either function directly as receptors or are linked to one)

receptors

ser/threonine phosphorylation represents the vast majority

tyrosine phosphorylation accounts for >0.1% but is a major player in signal transduction

kinases> phosphate ON >>>>> phosphatases> phosphate OFF

•some kinases are activated by phosphorylation

•phosphatases also inactivate kinases that themselves are activated by phosphorylation

•some phosphatases are inactivated by phosphorylation

how do "G proteins" (GTP-binding proteins) work

Gproteins

G proteins have helpers:

•protein kinase C (PKC): in cell culture analyses, commonly activated by phorbol esters (derived from plants, present permanent membrane binding site that looks like DAG) and calcium influx (either by ionophore or thapsigargin)

•cAMP signalling pathway: in cell culture analyses, commonly activated by forskolin (promotes cyclase activity) or by dibutyryl cyclic AMP (dbcAMP), which cannot be linearized by cells and therefore presents permanent "on" switch.

cAMP, or its analogues, activates protein kinase A (PKA, or cAMP-dependent kinase)

A typical consequence of "upstream" kinase activation:

glycolysis

Phosphatases reverse the effect of kinases

Calcium, calmodulin kinase (CaM kinase): commonly activated by calcium influx, must employ specific inhibitors of PKC, CaM kinase to discern between them in tests within intact cells (SLIDE)

CaM kinase =a kinase with a memory

•MAPkinase pathway: can be activated by PKC via cross-talk. otherwise by particular, monomeric G-protein linked receptors.

many of these elements discovered in Drosoph and/or yeast. (BOSS)

sevenless, son of sevenless Homologs in man

signal amplification (radiating from one to many as go downstream)

includes inactive kinase A splits to two

sometimes, signal integration (need 2 or more events to continue stream)

enzyme-linked (internal portion = linked to G protein)

or receptor DIMERIZATION creates a tyrosine kinase (note how very difficult to generate kinase activity just by receptor binding of distal domain

receptors for most growth factors = tyrosine kinases:>>>>>>downstream pathways