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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

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signaling from the cell surface to the nucleus
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

slide2

SIGNALING PATHWAYS LEADING TO ACTIVATION OF TRANSCRIPTION FACTORS AND MODULATION OF GENE EXPRESSION FOLLOWING LIGAND BINDING TO CERTAIN GS PROTEIN–LINKED RECEPTORS

slide3

TGF-b: Key Roles in Controlling

Cell Proliferation and Synthesis of the

Extracellular Matrix

TGF-b1

Hinck et al., (1996) Biochemistry

THE TGF- ß SUPERFAMILY INCLUDES

TGF- ß1, TGF- ß2, TGF- ß3, ACTIVIN, INHIBIN, MULLERIAN INHIBITING

SUBSTANCE,

AND AT LEAST 16

BONE MORPHOGENETIC PROTEINS

tgf b key roles in controlling cell proliferation and synthesis of the extracellular matrix
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

slide5
Schematic diagram of formation of mature dimeric TGFb proteins from secreted monomeric TGFb precursors.
the tgf b signaling pathway
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

combinatorial activation of transcription by smad proteins
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.

slide11

Human Diseases with Alterations

in the TGF-b Signaling Pathway

signaling from the cell surface to the nucleus12
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

hematopoiesis

EPO ACTS TO STIMULATE

THE PROLIFERATION

AND DIFFERENTIATION

OF ERYTHROID

PROGENITOR

CELLS TO MATURE

RED CELLS

HEMATOPOIESIS
slide16
EPO “GENE KNOCK- OUT” MICE ARE NORMAL EXCEPT THEY HAVE NO ADULT- TYPE RED BLOOD CELLS AND DIE AT EMBRYONIC DAY 14
structure of human growth hormone
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

structure of the external segment of the human growth hormone receptor
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

slide21
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

signal transduction proteins that bind to the cytosolic domain of the erythropoietin receptor
SIGNAL TRANSDUCTION PROTEINS THAT BIND TO THE CYTOSOLIC DOMAIN OF THE ERYTHROPOIETIN RECEPTOR
signal transduction by the epo receptor
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

model of an sh2 domain bound to a short target peptide
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.

dimerization of stat proteins leads to formation of a functionally active transcription factor
DIMERIZATION OF STAT PROTEINS LEADS TO FORMATION OF A FUNCTIONALLY ACTIVE TRANSCRIPTION FACTOR
general structure and activation of receptor tyrosine kinases rtks
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

slide34

Structures of MAP kinase in its inactive, unphosphorylated form and active, phosphorylated formPhosphorylation of MAP kinase by MEK at tyrosine 185 (pY185) and threonine 183 (pT183) leads to a marked conformational change in the phosphorylation lip (red).

slide35
Cycling of the Ras protein between the inactive form with bound GDP and the active form with bound GTP
slide39
Signaling pathways leading to activation of transcription factors and modulation of gene expression following ligand binding to RTKs
ubiquitin mediated pathway for degradation of cellular proteins
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.

activation of the transcription factor nf k b
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.