Slide set 9 Flashcards
Intracellular signaling pathway activated by an extracellular signal molecule
- Signal molecule binds to a receptor protein in plasma membrane of target cell (on cell surface)
- Receptor activates 1 or more intracellular signaling pathways
- involves a series of signaling proteins
- 1 or more of the intracellular signaling proteins alters activity of effector proteins
- this alters the behavior of the cell
types of effector proteins
transcription regulators, ion channels, components of metabolic pathways, or parts of the cytoskeleton
contact-dependent signaling
requires cells in membrane-membrane contact
paracrine signaling
local mediators (molecules secreted into extracellular space)
released into extracellular space and act on neighboring cells
synaptic signaling
neurons transmit signals electrically along their axons and release NTs at synapses
synapses are often located far away from neuronal cell body
Endocrine signaling
autocrine signaling
signaling and target cells are same cell type
EX: cancer
cell-surface receptors
- most signal molecs are hydrophilic (Can’t cross target cell’s plasma membrane)
- bind to signal molecule extracellularly
- binding changes target cell in some way
intracellular receptors
- small signal molecs diffuse across plasma membrane
- bind to receptor proteins in cytosol OR nucleus
- signal molecs are hydrophobic and poorly soluble in aqueous solns
- molecs are transported into blood and extracellular fluids while bound to carrier proteins
- dissociate from carried proteins before entering target cell
how do cells decide on the appropriate cellular response
integrate MULTIPLE SIGNALS
if a cell doesn’t receive the required survival signals, its undergoes apoptosis (cellular suicide)
some extracellular signals are inhibitory
cell surviving vs growing and dividing
depends on PI-3-Kinase/Akt/mTOR pathway
Survival pathway
PI-3-Kinase-Akt signaling pathway: survival, growth, and division
IGF’s
insulin-like growth factor (IGF) signal proteins
stimulate animal cells to survive and grow
bind to specific RTKs that active PI-3-Kinase to produce PI(3,4,5)P3
PI(3,4,5)P3 recruits 2 protein kinases to plasma membrane via their PH domains (Akt and PDK1)
Akt is now active and phosphorylates target proteins at plasma membrane, cytosol, and nucleus
target cells now have enhanced cell survival and growth!
PDK1 aka
phosphoinositide-dependent protein kinase
Akt aka
protein kinase B (PKB)
survival pathway
- Extracellular survival signal activates an RTK
- RTK recruits and activates PI 3-kinase
- PI-3-kinase produces PI(3,4,5)P3 (a docking site for 2 serine-threonine kinases with PH domains)
- Akt and PDK1 are brought into proximity at plasma membrane
- Akt is phosphorylated on a serine by a third kinase (mTOR in complex 2)
- this alters conformation of Akt so it can be phosphorylated on a threonine by PDK1
- PDK1 activates Akt
- active Akt dissociates from plasma membrane and phosphorylates target proteins (EX: Bad protein)
- Bad holds one or more apoptosis-inhibitory proteins (of Bcl2 family) in an inactive state
- phosphorylated Bad releases inhibitory proteins
- they now block apoptosis and thus promote cell survival
- phosphorylated Bad is bind to ubiquitous cytosolic protein 14-3-3 which keeps bad out of action
Bad protein
- targeted by Akt for phosphorylation
- Bad holds one or more apoptosis-inhibitory proteins (of Bcl2 family) in an inactive state
- phosphorylated Bad releases inhibitory proteins
- they now block apoptosis and thus promote cell survival
- phosphorylated Bad binds to ubiquitous cytosolic protein 14-3-3 to become inactive
- active Bad = phosphorylated
- inactive Bad = bound to ubiquitous cytosolic protein 14-3-3
survival vs growth pathways
Without extracellular growth factor
- Tsc2 (a Rheb-GAP) keeps Rheb inactive AND mTOR in complex 1 is inactive: there is no cell growth!
With extracellular growth factor
- active Akt phosphorylates and inhibits Tsc2 (promotes activation of Rheb)
- active Rheb (Rheb-GTP) helps activate mTOR in complex 1: stimulates cell growth