SIGNALING FROM THE CELL SURFACE TO THE NUCLEUS

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SIGNALING FROM THE CELL SURFACE TO THE NUCLEUS
PROTEIN KINASE A PHOSPHORYLATION AND
ACTIVATION OF CREB TRANSCRIPTION FACTOR
RECEPTOR SERINE KINASES - RECEPTORS FOR THE TGF-ß
SUPERFAMILY PHOSPHORYLATION AND ACTIVATION OF
SMAD TRANSCRIPTION FACTORS PARTNERING WITH
OTHER TRANSCRIPTION FACTORS TO ACTIVATE
TRANSCRIPTION OF SPECIFIC GENES PROTEIN-
TYROSINE KINASE RECEPTORS RECEPTORS LINKED TO
PROTEIN- TYROSINE KINASES - THE CYTOKINE
RECEPTOR SUPERFAMILY RECEPTORS LINKED TO
PROTEOSOME- MEDIATED DEGRADATION OF INHIBITORS OF
SPECIFIC TRANSCRIPTION FACTORS
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SIGNALING PATHWAYS LEADING TO ACTIVATION OF
TRANSCRIPTION FACTORS AND MODULATION OF GENE
EXPRESSION FOLLOWING LIGAND BINDING TO CERTAIN GS
PROTEINLINKED RECEPTORS
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THE TGF- ß SUPERFAMILY INCLUDES TGF- ß1, TGF-
ß2, TGF- ß3, ACTIVIN, INHIBIN, MULLERIAN
INHIBITING SUBSTANCE, AND AT LEAST 16 BONE
MORPHOGENETIC PROTEINS
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TGF-b Key Roles in Controlling Cell
Proliferation and Synthesis of the Extracellular
Matrix
BIOLOGICAL FUNCTIONS OF TGF-ß INCLUDE
INHIBITION OF CELL PROLIFERATION INDUCES
INHIBITORS OF CYCLIN - DEPENDENT KINASES TYPE
II RECEPTOR FREQUENTLY LOST OR MUTATED IN
CANCERS INDUCTION OF SYNTHESIS OF
EXTRACELLULAR MATRIX PROTEINS FIBRONECTIN,
COLLAGENS, PROTEOGLYCANS INHIBITION OF
SYNTHESIS OF EXTRACELLULAR PROTEASES COLLAGENASE
, PLASMINOGEN ACTIVATOR INDUCTION OF SYNTHESIS
OF INHIBITORS OF EXTRACELLULAR PROTEASES
PROMOTION OF CELL MATRIX AND CELL- CELL ATTACHMENT
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Schematic diagram of formation of mature dimeric
TGFb proteins from secreted monomeric TGFb
precursors.
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THE TGFb SIGNALING PATHWAY
TGFb SIGNALS THROUGH HETEROMERIC COMPLEXES OF
TYPES I AND II SERINE/THREONINE KINASE
RECEPTORS, LEADING TO PHOSPHORYLATION OF
EITHER SMAD2 OR SMAD3. A COMPLEX OF ONE OF
THESE PHOSPHORYLATED SMAD PROTEINS AND SMAD4
THEN TRANSLOCATES TO THE NUCLEUS, WHERE IT
BINDS TO OTHER TRANSCRIPTION FACTORS TO
ACTIVATE TRANSCRIPTION OF A VARIETY OF GENES
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THE TGFb SIGNALING PATHWAY
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COMBINATORIAL ACTIVATION OF TRANSCRIPTION BY SMAD
PROTEINS
SMAD3 PROTEINS BIND ONLY TO 4 BASE PAIRS OF DNA
5 AGAC 3 EACH TFE3 TRANSCRIPTION FACTOR BINDS
TO A 3 BASE PAIR SEQUENCE 5 CAC 3 A DIMER OF
TWO TFE3s BINDS TO A 6 BASE PAIR SEQUENCE 5
CACGTG 3 (GTG IS THE COMPLEMENT OF CAC) THUS A
SEQUENCE 5 AGACxxxCACGTG 3 BINDS ONE SMAD3
PROTEIN AND ONE TFE3 DIMER IN A PRECISE
ARRANGEMENT, ALLOWING FOR TRANSCRIPTION
ACTIVATION, IN THIS CASE OF THE PAI-1 GENE.
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SIGNALING FROM THE CELL SURFACE TO THE NUCLEUS
RECEPTORS LINKED TO PROTEIN- TYROSINE KINASES
- THE CYTOKINE RECEPTOR SUPERFAMILY
PHOSPHOTYROSINE RESIDUES BINDING TO SPECIFIC SH2
DOMAINS ACTIVATION OF STAT TRANSCRIPTION
FACTORS PARTNERING OF STATs WITH OTHER
TRANSCRIPTION FACTORS TERMINATION OF SIGNALING
BY ACTIVATION OF PROTEIN TYROSINE PHOSPHATASES
INHIBTION OF SIGNALING BY PROTEINS CONTAINING
ONLY SH2 DOMAINS RECEPTORS LINKED TO
PROTEOSOME- MEDIATED DEGRADATION OF INHIBITORS OF
CERTAIN TRANSCRIPTION FACTORS
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HEMATOPOIESIS
EPO ACTS TO STIMULATE THE PROLIFERATION AND
DIFFERENTIATION OF ERYTHROID PROGENITOR CELLS
TO MATURE RED CELLS
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EPO GENE KNOCK- OUT MICE ARE NORMAL EXCEPT THEY
HAVE NO ADULT- TYPE RED BLOOD CELLS AND DIE AT
EMBRYONIC DAY 14
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STRUCTURE OF HUMAN GROWTH HORMONE
LIKE EPO AND OTHER CYTIOKINES, GROWTH HORMONE
FORMS A 4- ALPHA HELIX BUNDLE. AMINO ACIDS THAT
BIND TO THE FIRST GROWTH HORMONE RECEPTOR ARE IN
GREEN THOSE THAT BIND TO THE SECOND GROWTH
HORMONE RECEPTOR ARE IN BLUE
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STRUCTURE OF THE EXTERNAL SEGMENT OF THE HUMAN
GROWTH HORMONE RECEPTOR
THE PLASMA MEMBRANE IS AT THE BOTTOM OF THE
FIGURE AMINO ACIDS THAT BIND GROWTH HORMONE ARE
IN BLUE AMINO ACIDS THAT BIND THE SECOND
MOLECULE OF GROWTH HORMONE RECEPTOR ARE IN
GREEN
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THREE- DIMENSIONAL STRUCTURE OF THE COMPLEX OF
ONE MOLECULE OF HUMAN GROWTH HORMONE AND TWO
GROWTH HORMONE RECEPTORS
PLASMA MEMBRANE IS AT THE BOTTOM OF THE FIGURE
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SIGNAL TRANSDUCTION PROTEINS THAT BIND TO THE
CYTOSOLIC DOMAIN OF THE ERYTHROPOIETIN RECEPTOR
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TWO POSSIBLE MECHANISMSBY WHICH EPO
ACTIVATESTHE EPO RECEPTOR
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SIGNAL TRANSDUCTION BY THE EPO RECEPTOR
ACTIVATED JAK2 PHOSPHORYLATES UP TO 8 TYROSINE
RESIDUES ON THE CYTOSOLOC DOMAIN OF THE EPO
RECEPTOR. EACH PHOSPHOTYROSINE CAN FORM THE
DOCKING SITE FOR THE SH2 DOMAIN OF A SIGNAL
TRANSDUCTION PROTEIN
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MODEL OF AN SH2 DOMAIN BOUND TO A SHORT TARGET
PEPTIDE. 
IN THIS TARGET PEPTIDE, THE PHOSPHOTYROSINE
(P-TYR) AND ISOLEUCINE (3ILE) FIT INTO A
TWO- PRONGED SOCKET ON THE SURFACE OF THE SH2
DOMAIN. THE PHOSPHATE GROUP COVALENTLY
ATTACHED TO THE TYROSINE RESIDUE IS LIGHT
BLUE.
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DIMERIZATION OF STAT PROTEINS LEADS TO FORMATION
OF A FUNCTIONALLY ACTIVE TRANSCRIPTION FACTOR
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TERMINATION OF SIGNAL TRANSDUCTION BY THE EPO
RECEPTOR
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TERMINATION OF SIGNAL TRANSDUCTION BY THE EPO
RECEPTOR 2
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GENERAL STRUCTURE AND ACTIVATION OF RECEPTOR
TYROSINE KINASES (RTKS)
AS WITH THE EPO RECEPTOR, LIGAND BINDING INDUCES
A CONFORMATIONAL CHANGE THAT PROMOTES OR
STABILIZES RECEPTOR DIMERS. THE KINASE ACTIVITY
OF EACH SUBUNIT OF THE DIMERIC RECEPTOR
INITIALLY PHOSPHORYLATES TYROSINE RESIDUES NEAR
THE CATALYTIC SITE IN THE OTHER SUBUNIT,
CAUSING ITS ACTIVATION. SUBSEQUENTLY, TYROSINE
RESIDUES IN OTHER PARTS OF THE CYTOSOLIC DOMAIN
BECOME PHOSPHORYLATED AND SERVE AS DOCKING
SITES FOR SH2 DOMAINS OF SIGNALING PROTEINS
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Structure of the FGF - FGR Receptor Complex
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Structures of MAP kinase in its inactive,
unphosphorylated form and active, phosphorylated
form Phosphorylation of MAP kinase by MEK at
tyrosine 185 (pY185) and threonine 183 (pT183)
leads to a marked conformational change in the
phosphorylation lip (red).
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Cycling of the Ras protein between the inactive
form with bound GDP and the active form with
bound GTP  
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Activation of Ras following binding of a ligand
to a RTK
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Model of SH3 domain bound to a short target
peptide 
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 Kinase cascade that transmits signals downstream
from activated Ras protein
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Signaling pathways leading to activation of
transcription factors and modulation of gene
expression following ligand binding to RTKs
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Activation of protein kinase B by the PI- 3
kinase signaling pathway (part 1). 
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Activation of protein kinase B by the PI- 3
kinase signaling pathway (part 2). 
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Cleavage of PIP2 by phospholipase C (PLC) yields
DAG and IP3.
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Elevation of cytosolic Ca2 via the
inositol-lipid signaling pathway
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UBIQUITIN-MEDIATED PATHWAY FOR DEGRADATION OF
CELLULAR PROTEINS
A CONJUGATING ENZYME CATALYZES FORMATION OF A
PEPTIDE BOND BETWEEN THE SMALL PROTEIN
UBIQUITIN (UB) AND THE SIDE-CHAIN NH2 OF A
LYSINE RESIDUE IN A TARGET PROTEIN. ADDITIONAL
UB MOLECULES ARE ADDED, FORMING A
MULTIUBIQUITIN CHAIN. THIS CHAIN DIRECTS THE
TAGGED PROTEIN TO A PROTEASOME, WHICH CLEAVES
THE PROTEIN INTO NUMEROUS SMALL PEPTIDE
FRAGMENTS. PROTEOLYSIS OF UBIQUITIN- TAGGED
PROTEINS OCCURS ALONG THE INNER WALL OF THE
CORE.
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ACTIVATION OF THE TRANSCRIPTION FACTOR NF-kB

MANY DIFFERENT EXTRACELLULAR SIGNALS CAN INDUCE
ACTIVATION OF NF-kB THESE SIGNALS ACTIVATE AN
I-kB KINASE COMPLEX. THIS COMPLEX
PHOSPHORYLATES TWO N-TERMINAL SERINE RESIDUES IN
I-kB. PHOSPHORYLATED I-kB IS UBIQUITINATED AND
SUBSEQUENTLY DEGRADED BY THE PROTEOSOME. REMOVAL
OF I-kB UNMASKS THE NUCLEAR LOCALIZATION SITES IN
BOTH THE P50 AND P65 SUBUNITS OF NF-kB. NF-kB
ENTERS THE NUCLEUS, BINDS TO SPECIFIC SEQUENCES
IN DNA AND REGULATES TRANSCRIPTION.