CellSignaling08Lec4 - Adaptor proteins can be composes...

Adaptor proteins – can be composes
almost entirely of SH2 and SH3
domains – work to Couple tyrosine-
phosphorylated proteins to other
proteins that do not have their own SH2
domains.
*** Important – because such adaptor
proteins help couple activated receptors
to RAS

RAS is a key component of many
receptor tyrosine kinase cascades.

RAS first discovered as a viral oncogene.
*subsequent studies indicate that an altered
(hyperactive) RAS gene is found in about 30%
of all human tumors.

RAS proteins belong to the large
superfamily of monomeric GTPases .

The RAS Superfamily
Ras H,K,N
Ras
Relay signals from
RTKs
Rho Rho,Rac,
Cdc42
Relay signals
ARF ARF1 -
ARF6
Vesicle protein coat
assembly
Rab Rab1 -
60
Vesicular trafficking
Ran Ran Mt assembly and
nuclear transport

EXAMPLE: Early Cell-signaling Events
in Drosophila Eye Development.
Sevenless

Ras Activates :
A Serine/Threonine phosphorylation
Cascade – MAP-Kinase.
MAP = M itogen- A ctivated P rotein
•
Many s/t kinases participate in the cascade.
•
Core module consists of 3 Kinases.
•
Terminal kinase is MAP-Kinase
•
**Unusual feature of MAP Kinase - requires
two phosphorylation events for full
activation.

Ras Activates :
A Serine/Threonine phosphorylation
Cascade – MAP-Kinase.

Inactive Raf
Active Raf
14-3-3
C-terminal
Kinase domain
N-terminal
Regulatory
domain

ATP
ADP
Raf activates MEK
MEK activates MAPK
ATP
ADP

There are multiple three component
MAP kinase signaling modules.
•
Different ones mediate different
responses in the same cell.
•
Can be activated by different receptors,
i.e. G-protein linked receptors in yeast.
•
Some of the MAP Kinase modules use
one or more of the same kinases – yet
activate different effector proteins.

Key Concept: Scaffold Proteins Help
Organize and Prevent Crosstalk
between parallel MAP Kinase Modules

Key Concept: The building of
Intracellular Signaling Complexes onto
scaffold proteins, enhances speed,
efficiency and specificity of the
response.

P
P
P
P
P
Tyr - 1009
Tyr - 771
Tyr - 751
Tyr- 740
Tyr - 1021
Phospholipase
C-
γ
GTPase-
activating protein
(GAP)
PI 3-kinase
(regulatory
subunit)
SH2
domains
SH3
domain
PDGF receptor

PI3-kinase – (phosphatidylinositol 3-
kinase) is involved in one of the major
intracellular signaling pathways that
leads to cell growth.
•
It principally phosphorylates inositol
phospholipids.
•
Can be activated by Receptor tyrosine
kinases, as well as others*.