Cell Signaling RTK Flashcards
Enzyme coupled receptors are
Large, heterogeneous family of transmembrane proteins that function as enzymes
“Single-pass” membrane proteins (typically)
Typically, act as protein kinases that phosphorylate specific sets of proteins in the target cell.
Single pass enzyme coupled receptors
Ligand-binding domain is on the
Catalytic site is on the
Ligand-binding domain on the extracellular side of the PM.
Catalytic site on the cytoplasmic side of the PM.
Receptor Tyrosine Kinases are
monomers (single units)
are single pass, do not have conformation changes/changes between subunits
For most receptor tyrosine kinases (RTKs), ligand binding causes receptors to
dimerize: bringing the two cytoplasmic kinase domains together. This causes trans autophosphorylation of the tyrosine residues - the R is activated
Phosphorylation at some tyrosines causes ___ while Phosphorylation at tyrosines (in other areas of the receptor) causes ___
in the kinase domains promotes the complete activation of the domains
Phosphorylation at tyrosines (in other areas of the receptor), generates a docking site for intracellular proteins.
- This leads to large signaling complexes which are recognized by intracellular signaling proteins.
Each signaling protein binds to
a particular phosphorylated site on the activated receptors.
(first the phosphorylation results in activation) the binding alone causes a conformation change, resulting in activation of the signaling protein
Insulin Receptor is always a
dimer (already as is/not activated)
Ligand binding of the insulin receptor causes ___
causes a conformational change that brings the two internal kinase domains closer together.
which results in Autophosphorylation of tyrosines in kinase active sites
Epidermal Growth Factor Receptor activation
is NOT activated by trans-autophosphorylation
Dimerization orients internal domains in an asymmetric dimer (activator pushes against receiver), Conformational change in receiver, which phosphorylates both receptors (itself and the activator)
RTK activation of Ras
RTK is activated (phosphorylated)
- adaptor protein Grb2 has a SH2 domain which binds to to the activated receptor, while one or both of its SH3 domains bind to Sos (a Ras GEF, also contains a PH domain that recognizes specific phospholipids) -
Sos activates the Ras protein (GDP to GTP) which is always membrane bound - resulting in downstream signals
Tyrosine phosphorylations and Ras triggered by activated RTKs are
short lived
To stimulate proliferation, short lived signals must be converted to long lasting signal-to be relayed to the nucleus (alter gene expression) which is done through
MAP kinase module
MAP kinase module: Mitogen activated protein kinase module
Ras activates (by phosphorylation) MAP Kinase Kinase kinas (Raf)
Raf activates MAP kinase kinase (Mek)
Mek activates MAP kinase (Erk)
Erk passes nuclear envelope, into nucleus
This pathway allows signaling in cell to be efficient
Regulation of the MAP kinase module
feedback loops
Positive MAP kinase module feedback loop
less common
signal kinase phosphorylates the kinase, resulting in it activating itself, this prolongs the signal/amplifies it
Negative MAP kinase module feedback loop
more common
signal kinase phosphorylates the e kinase is activated, there is a delay then the neg. loop - causing the phosphorylation/activation of the phosphatase, this removed /deactivates the e kinase
Negative feedback with a long delay can produce responses that oscillate
Feedback loop from growth factor to phosphatase
Proto-oncogenes are the genes that normally
control how often a cell divides and the degree to which it differentiates (or specializes).
Oncogene is
Permanently “turned on” or activated
when it is not supposed to be. - increasing cell growth and division
gain of function mutation of proto oncogenes causes oncogene
Proto oncogenes on the normal growth control pathway
anything on pathway - signaling enzymes, transcription factors
Ras oncogenes are cause by ___
result in ____
point mutations create a hyperactive Ras (GTPase) that can not shut itself off by hydrolyzing bound GTP to GDP
result in constant signaling for cell growth and proliferation - stimulates growth even when no growth factor is present.
Examples of molecules that could inhibit specific oncogenic proteins
Many cancers lack an oncogenic mutation in ___ but Most tumors contain ____
a protein kinase
inappropriately activated signaling pathways, for which a target in the pathway may be identified
the generation of phosphoinositide docking sites by PI 3-kinase
PI ->(PIP->PIP2)-> PI(3,4,5)P3 - can serve as a docking site for signaling proteins
How Signaling through PI 3-kinase promotes cell survival
extracellular survival signal activates RTK, recruits and activates PI 3-kinase.
The PI 3-kinase produces PI(3,4,5)P3, which serves as a docking site for two serine/threonine kinases with PH domains—Akt and the phosphoinositide-dependent kinase PDK1—and brings them into proximity at the plasma membrane.
The Akt is phosphorylated on a serine by a third membrane-associated kinase (mTOR), which alters the conformation of the Akt so that it can be phosphorylated on a threonine by PDK1, which activates the Akt.
The activated Akt now dissociates from the plasma membrane and phosphorylates various target proteins, including the Bad protein.
When unphosphorylated, Bad holds the apoptosis-inhibitory Bcl2 in an inactive state. Once phosphorylated, Bad releases Bcl2, which now can block apoptosis and thereby promote cell survival.
The phosphorylated Bad binds to a ubiquitous cytosolic protein called 14-3-3, which inhibits bad.
IP3 carries phosphates at positions ____ on the inositol ring. Phosphorylation by ____ puts a phosphate on position____of the inositol ring
1, 4, and 5
PI 3-kinase
3
