Download L04 - Extracellular Signal Receptors II

Lecture 04 – Extracellular Signal Receptors II
BIOL 5190/6190 Cellular & Molecular Singal Transduction
Prepared by Bob Locy
Last modified -13F
Extracellular Signal Receptors II
1. Integrin receptors
• Extracellular matrix signaling – two-way
• Obligate heterodimers – bent structure with 1 MSD
2. Toll gate receptors
Integin Signaling pathways
• Integrins are cell surface receptors that
interact with the extracellular matrix
and mediate intracellular signals in
response to the extracellular matrix
including cellular shape, mobility, and
progression through the cell cycle.
• Integrins do not themselves possess a
kinase domain or enzymatic activity but
rely on association with other signaling
molecules to transmit signals.
• Interactions between the extracellular
matrix and the actin cytoskeleton
commonly take place at focal adhesions
on the cell surface that contain localized
concentrations of integrins, signaling
molecules, and cytoskeletal elements.
Integin Signaling pathways
• Talin forms a direct interaction with the
integrin cytoplasmic domain, and
interacts with cytoskeletal elements
(actin) and signaling factors.
• Paxillin and CAS also localize in focal
adhesions and may serve as a scaffold
for other integrin signaling components
like FAK and src.
• Interaction of FAK, CAS and src may be
required for integrin regulation of cell
cycle progression.
• The CrkL adaptor protein may regulate
downstream integrin signaling.
• Growth factor signaling pathways and
the caveolin receptor exhibit important
cross talk with integrin receptors in
cellular responses like activation of map
kinase, proliferation and motility.
Integin Signaling pathways
• Complexity
Extracellular Signal Receptors II
1. Integrin receptors
2. Toll gate receptors – (Toll-like receptors)
• PAMPS involvement – primitive immune function
• TLRs recognize non-self moleucles, and respond by inititating
responses
• TLRs are single membrane spanning domain proteins (not kinases)
• TLRs by virtue of a conformational change when ligands bind,
cause changes in one or more “adapter protein” that can
subsequently activate additional response regulators including
map kinases and other protein kinases leading to changes in gene
expression.
TolI gate receptor pathways
• Simple view: (MyD88-dependent
pathway)
• Ligand recognition by TLR4 or any other
TLR dimer (except TLR3) lead to MyD88
conformational changes
• MyD88 activates IRAK1, 2, & 4 (protein
kinases)
• These phosphorylate and activate TRAF6
• TRAF6 polyunbiquinates TAK1
• TAK1 binds & phosphorylates IKK
• And leads to phosphorylation &
degradation of IkB and allows NFkB to
difuse into the nucleus where it promotes
synthesis of inflammatory cytokines.
TolI gate receptor pathways
• Simple view: (TRIF-dependent
pathway, TLR3 & TLR4)
• Triggered by dsRNA or LPS
• Ligand recognition by TLR4 (LPS) or
TLR3 (dsRNA) leads to TRIF
conformational changes which activate
TBK1 & possibly RIP1 (ambiguous)
• TBK1 leads to phosphorylation of IRF3,
which leads to translocation to the
nucleus and type 1 interferon
production.
• RIP activates PI3K and Akt, and MAP
kinase cascades are also involved, but
details vary for specific receptors.
TolI gate receptor pathways