Signal Transduction I

Receptors & Ligands

Signal Transduction

Signal Transduction Pathway Overview

• agonists• receptors• 2nd messengers• cytoplasmic

transducers/effectors

• targets

The Usual Suspects

Seven Lively Helices

Seven-Helix Receptor Family

• All 7-pass receptors interact with heterotrimeric G-proteins ()• ligand binding triggers release of regulatory subunits and

GDPGTP exchange G-protein subunit then activates adenyl cyclase and

phopholipases to produce 2nd messengers cAMP & DAG respectively

• These 2nd messengers activate PKA and PKC respectively which phosphorylate targets and the C-term of 7-pass receptor

Receptor Tyrosine Kinases

Some Domains

RTK Signaling

• ligand binding induces dimerization

• transphophorylation• phosphorylated residues

serve as binding motifsfor transducer proteins

RTK- Ras Pathway

GAP

Grb2,Shc

GEF like Sos

GEF

Jak Activation

Receptor-JAK-Stat pathway

Receptor S/T Kinases

• Ligands are all members of TGF- superfamily

Receptor Guanylyl Cyclases

• binding of ligand induces guanylyl cyclase activity

• These can be TM or cytoplasmic receptors

• atrial natriuretic factor receptor is TM

• NO receptor is cytoplasmic

TNF Receptor Family

• All transduce survival/death signals

Juxtacrine Signaling: Notch Pathway

Secreted Signaling Molecules

• FGF Family

• Hedgehog Family

• Wnt Family

• TGF Superfamily– TGF Family– Activin Family– BMP Family

• EGF Family• PDGF Family• Retinoids• HGF/Scatter Factor• Neurotrophins• Semaphorins• Cytokines

Receptors for Soluble Signaling Molecules

• Receptor Tyrosine Kinase (RTK) pathway– FGFR, EGFR, PDGFR– Receptor coupled to ras

signal transduction cascade

• Smad pathway– Bipartite Serine/Threonine

Kinase Receptors– AcRI/II, TGFRI/II,

BMPRI/IIs– Receptors activate Smad

transcription factors

• Wnt--catenin pathway– Frizzled family of receptors– Activation of pathway allows

-catenin to enter nucleus

• JAK-STAT pathway– Peptide hormone or cytokine

receptor coupled to a Jak cytoplasmic tyrosine kinase

– Jaks activate STAT transcription factors

• Hedgehog Pathway– Patched and smoothened co-

receptors– Activation of pathway converts

Ci txn’l repressor to activator

• Steroids/Retinoids– Nuclear/DNA binding

receptors– Hormone permits entry into

nucleus, alters DNA binding conformation, or allows interaction with co-txn factors

Cell Associated Signaling Molecules

• ECM (ligand)

– Fibronectin– Laminin– Type IV collagen

• Integrins (receptor)

• CAMs (receptor)

•Notch Family (receptor)

•Delta Family (ligand)

•Eph Family (receptor)

•Ephrin Family (ligand)

Generalized Signal Transduction