Lecture 04 – Extracellular Signal Receptors II

1. Lecture 04 – Extracellular Signal Receptors II BIOL 5190/6190 Cellular & Molecular Singal Transduction Prepared by Bob Locy Last modified -13F

2. Extracellular Signal Receptors II • Integrin receptors • Extracellular matrix signaling – two-way • Obligate heterodimers – bent structure with 1 MSD • Toll gate receptors

3. 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.

4. Integin Signaling pathways • Talin forms a direct interaction with the integrincytoplasmic domain, and interacts with cytoskeletal elements (actin) and signaling factors. • Paxillinand 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.

5. Integin Signaling pathways • Complexity

6. Extracellular Signal Receptors II • Integrin receptors • 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.

7. 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.

8. 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.

9. TolI gate receptor pathways