signal transduction diagrams

Signaling Molecules– Ion channel linked receptors – Enzyme-linked receptors: single pass ● intrinsic enzyme activities ● coupled to intracellular enzymes – G-protein coupled: 7-pass serp

Signaling Molecules:

Roles in Differentiation and

Proliferation

Signaling Molecules

– Ion channel linked receptors

– Enzyme-linked receptors: single pass

● intrinsic enzyme activities

● coupled to intracellular enzymes

– G-protein coupled: 7-pass serpentine

– Cytoplasmic and nuclear receptors

● Cytoplasmic transducers

● Nuclear targets

Ion Channel Linked Receptors

! Commonly called transmitter-gated ion

channels or ionotropic receptors

! Involved in rapid synaptic signaling

! Classically defined by acetylcholine (ACh)

receptor at neuromuscular junction

! Nerve impulse depolarizes axon, signal travels to nerve terminal leading to opening of voltage-gated

Ca2+ channels, Ca2+ flows in and ACh is released

! ACh binds receptors on muscle cells leading to

opening of cation channel and Na+ flows in

Receptors Associated with Enzyme Activity

● Y kinases: 9 different classes

– eg PDGF, FGF, insulin, EGF

Receptors with Tyrosine Kinase Activity

Coupling insulin binding to multiple signal pathways

SH-2 groups on proteins bind phosphotyrosine

SH-3 groups on proteins bind proline-rich regions

GGGG Protein Coupling

● activation of adenylate cylcase

– eg, glucagon receptor

● activation of PLC γ

– eg, angiotensin, vasopressin, bradykinin

● activation of phosphodiesterase

– transducin in photoreception

Glucagon and epinephrine as examples of

cAMP-mediated signaling

GGGG Protein Regulators

● GAPs: GTPase activating proteins

– eg, rasGAP

– NF1 (neurofibromin) a tumor suppressor

G Protein cycle of activation and

inactivation

G Proteins contain intrinsic GTPase activity

Activation of Ras signaling

pathway by an RTK

Phosphotyrosine on receptor is bound by adaptor protein,

which binds and

activates Guanine Nucleotide

Releasing Protein (GNRP) (also GEF) GNRP activates

Ras; Ras activates a kinase cascade.

Ras GTPase is

activated by GAP, turning the pathway off.

Ras activation of MAP Kinase

Once Ras is activated, it

activates a series of kinases, beginning with the Raf kinase (MAPKKK)

Raf activates MAPKK (MEK)

MAPKK activates MAPK

(ERK)

MAPK activates transcription factors

Activation of STAT

signaling

Receptor-associated PTK

is activated and phosphorylates STAT proteins (Signal

Transduction and Activator of

Transcription), which dimerize and translocate to nucleus where they function as transcription

factors

Signaling by Transforming Growth Factor- β superfamily receptors Smad proteins phosphorylated (note S/T intrinsic kinase) by dimerized receptors; Smad complexes act as transcription factors

Cadherins Cell Adhesion Molecules

Activation of signal transduction via cell adhesion molecules

Integrin-mediated signaling through associated Tyr-PK

Another example of signaling through integrins via

associated PTK

Convergence, Divergence, and Crosstalk

in signal transduction pathways

Signal Divergence, Convergence, and Cross talk

from PDGF Receptor

Convergence of signals to the Ras pathway

Signal

divergence from insulin receptor

Vasculogenesis and Angiogenesis

Vasculogenesis involves formation of initial blood islands and construction

of capillary networks

Angiogenesis involves formation of new blood vessels.

Nitric Oxide (NO) signaling

NO can act as a

diffusible messenger

● reside in cytoplasm, bind ligand then

migrate to nucleus where they interact with specific DNA sequences

Steroid Hormone Receptors

Receptor Binding Proteins

! Other binding proteins

include:

– Hsp70

– FKBP (immunophilin)

– p23

! Functions of the binding

proteins are unclear

– Receptor trafficking

! Binding proteins dissociate

upon ligand binding

APC in GI Cancers

! FAP due to germline mutations in APC

! Somatic (sporadic) mutations in the

APC gene initiate colorectal malignancy

! APC mutations in 63% of colonic

adenomas

! 99% of germline and 100% of sporadic APC mutations lead to truncated protein

Significance of Signal Transduction to Disease:

Tumorigenesis

● Cancer cells contain genetic damage

● many of the genes encoding signaling

molecules have been shown to be capable of causing cancer if disrupted in some way

APC Function

! APC associates with β-catenin, a protein

involved in the Wnt signaling pathway

! APC induces β-catenin phos leading to its

Wnt signaling

β -catenin bound in complex which includes GSK-3; this kinase phosphorylates β -

catenin leading to its

degradation.

Activation of disheveled

causes inhibition of GSK-3.

β -catenin builds up, is

released from complex, and translocates to nucleus

where it forms part of a

transcription factor complex

to activate gene expression

Chronic Myeloid Leukemia

! CML results from a translocation between

chromosomes 9 and 22

! Result is termed the Ph + chromosome

! ABL gene on chromosome 9 placed next to BRC gene on 22 results in a fusion protein bcr-abl

! abl is a non-receptor Y-kinase

! bcr is member of the Rho family of small GTPases

! Similar translocation occurs in ALL

! CML is target of Y-kinase inhibitor Glivec

! Also found in Burkitt lymphoma

! MYC on 8 placed near immunoglobulin heavy chain gene enhancer on 14

! Another common translocation is t(14;18)

! BCL2 gene on 18 is disrupted, bcl2 involved

in control of apoptosis, disruption leads to

loss of induced apoptosis