Costimulation causing PIP3 Kinase which starts the whole cascade PLC-y main contributor

Lecture 12

TCR signaling produces DAG (membrane lipid) which recruits RasGRP where it activates ______. Ras activates ____ which phosphorylates ___, which phosphorylates ___. Activated ___ allows it to enter the nucleus where it phosphorylates transcription factor ___. ____ stimulates the transcription factor ____ gene. JNK is activated and goes into the nucleus and phosphorylates ___ creating the dimer ___ which initiates the transcription of ___

RasGRP, Ras, Raf, Mek, Erk, Erk, Elk-1, Elk-1, FOS, c-jun, AP-1, IL-2

DAG recruits PKC-0 to the membrane where it phosphorylates _____, creating a scaffold ___ and ____. This recruits ____ which makes a polyubiquitin scaffold on itself _____. ____ binds and rectruits ____ to the ubiquitin. TAK1 phosphorylates ____ which phosphorylates IkB. This initiates IkB, which resides in the active site of NFkB, for _____ and degradation. Degradation of ___ releases ____ letting it go to the nucleus to initiate transcription factor gene ____

CARMA1, BCL10 and MALT1, TRAF-6, NEMO, TAB 1/2, TAK1, IKK-B, ubiquitination, IkB, NFkB, IL-2

CD4 tcells have ____ receptors that the APC has the Ligands ___ or ___ that interact during costimulation. ____ binding initiates the phosphorylation of CD28. This attracts and activates ____ kinase that phosphorylated PIP2 to PIP3. PIP3 attracts ____, ____, ____ and ___. ____ phosphorylates PLCy. Vav leads to ____ activation.

CD28, CD80, CD86, CD80, PIP3, PDK1, Akt, ltk, Vav, Itk, Cdc24

TCR and CD28 activate ____ which cleaves PIP3 into two products ___ and ___. One product ___ leads to the accumulation of ___ which leads to the transcription factor ____. The other product ___ attracts ____ leading to downstream transcription factor_____. This cleaved product also attracts a second molecule ____ which signals downstream to the transcription factor _____. All of these transcription factors signal to transcribe the gene ____

PLC-y, IP3 and DAG, IP3 and Ca2, NFAT, DAG, RasGRP, AP-1, PKC-0, NFkB, IL-2

TCR signaling intiation requires coreceptor ___ and _____

Lck and ZAP-70

Lck is a ____ associated w ____ and ____ coreceptors on Tcells

Kinase, CD4, CD8

TCR and coreceptors contain _____ in the intracellular region where ____ are located

Zeta chain, ITAMs

ITAMs stand for

immunoreceptor tyrosine-based activation motifs

Lck phosphorylates the _____ in the TCR upon co-receptor engagement (CD4) with the antigen: MHC

ITAMs

ZAP-70 is recruited by ______ _____ domains to the ITAMs and is also _______ by Lck

tandem SH2 (containing 2 phosphates), phosphorylated

After ZAP70 is phosphorylated (activated) by Lck, ZAP70 phosphorylates _____ and _____

LAT and SLP-76

LAT is a ____ protein and SLP-76 is a _____ protein

Scaffold, Adaptor

After ZAP70 phosphorylates the scaffold and adaptor proteins, this ______ 4 signaling modules

initiates

#1 signaling module of ZAP-70, is ___ activation which leads to increased metabolic activity. This is due to ZAP-70 phosphorylating ___ kinase which converts PIP2 to PIP3 to bind to the ____ domain of ____

Akt, PIP3, PH of Akt

#2 signaling module ZAP-70 phosphorylates the scaffold protein ____, which creates docking sites for ____ which leads to _______ factor activation

LAT, PLC-y, transcription

#3 signaling module of ZAP-70 leads to _____ which leads to _______ activation/ _____ reorganization

VAV, actin, cytoskeletal

#4 signal module of ZAP-70 involves ____ recruitment and enhances ____ adhesiveness and clustering

ADAP, integrin

Stage 1: IPC-y activation generates cleavage of _____ to make _____ and _____ leading to 3 pathways for transcription activation

PIP2, IP3, DAG

PATHWAY 1/ 2ND SIGNALING MODULE: ____ diffuses through cytosol, and _____ is retained at the ______ ______

IP3, DAG, plasma membrane

PATHWAY 2/ 2ND SIGNALING MODULE: After IP3 and DAG are made from PLC-y, ____ binds to the IP3 receptor and opens calcium channels to release it from the ER to the cytosol. Depletion of Ca2 from ER leads to _____ ______

IP3, ORAI1, STIM1 aggregation

PATHWAY 3 / 2ND SIGNALING MODULE: Aggregated STIM1 binds to and opens _____ channels in the plasma membrane allowing extracellular Ca2+ to ______.

Dag which is retained at the plasma membrane recruits ____ and _____

ORAI1, enter, RasGRP and PKT O

Phosphorylation of ____ and ____ keeps NFAT in the cytoplasm of ______ cells

Ser, Thr, unstimulated

Ca2 entry (caused from STIM1) activates the Ser and Thr phosphatase which dephosphorylates ______, which then enters the ____ and activates ____ _____ of IL-__

NFAT, nucleus, gene transcription of IL-2