Important Facts Flashcards
Serine/threonine kinases
Raf kinase / BRAF
Akt/PKB (known as Akt)
CDKs
MEK - technically dual specificity - serine/threonine and tyrosine
Receptor tyrosine kinases
c-Kit
Insulin receptor
EGFR
PDGFR
MEK - technically dual specificity - serine/threonine and tyrosine
ABL
**JAKs are non-receptor tyrosine kinases
**FAK is a non-receptor tyrosine kinase
JAKs include receptors for
Interferon (IFN)
Erythropoietin (EPO)
Thrombopoietin (TPO)
Tumor suppress genes/proteins
Retinoblastoma protein
p53
PTEN
CDKN2A
NF1
APC
KEAP1
Growth inhibitory factors
TGF-beta (to normal cells, but can foster tumor progression by activating EMT)
3 different DNA tumor virus oncoproteins
EIA (from human adenovirus type 5)
Large T antigen (from SV40 virus)
E7 oncoprotein (from HPV)
Transcription factors
E2Fs
Pro apoptotic proteins
Bax and Bak
Fas ligand (CD95 or FasL) and its interaction with the Fas receptor
tumor necrosis factor (TNF) and its receptor interaction
Anti-apoptotic
Bcl-2, Bcl-XL, and Mcl1
Mitogenic growth factors
Hepatocyte growth factor (HGF)
Transforming growth factor-alpha (TGF-alpha)
Platelet derived growth factor (PDGF)
Trophic factors
IGF-1
IGF-2
Anti-angiogenic factors
Thrombospondin-1 (Tsp-1)
Pro-angiogenic factors
VEGF (with HIF-1alpha transcription factor and VHL tumor suppressor)
TGF-alpha
TGF-beta
TNF-alpha
G-CSF
PDGF-Beta and PDGFR
IL-8
HGF
Angiopoietin 1 and 2 (and their receptors Tie-1 and Tie-2)
Monoclonal antibodies and targets
bevacizumab (Avastin) = VEGF-A
IHCs
Vimentin - mesenchymal cells
Cytokeratin - epithelial cells
CD204 - histiocytic sarcoma
Jak2/STAT5 is usually responsive to what interleukins
IL-2
IL-3
IL-6
Death receptors
Fas receptors
TNF receptors
Type 1 small molecule inhibitors
Toceranib
Type 2 small molecule inhibitors
Type III small molecule inhibitors
Covalent inhibitors (small molecule inhibitors)
ibrutinib, afatinib
**irreversible
Palladia targets what TKRs
Kit
PDGFR
VEGF
FLT3
CSF1R
Pro-inflammatory cytokines
TNF-alpha - mediator of acute inflammatory response to bacteria; produced by macs and DCs; 2 forms (type I and type II)
IL-1 - acute inflammation; produced by activated mononuclear phagocytes, neuts, epithelial cells, endothelial cells; 2 forms (alpha and beta); binds to cell receptors leading to activation of NF-kB and AP1
IL-6 - acute inflammation; produced by phagocytes, vascular endothelium, fibroblasts; made in response to PAMPs, IL-1, TNF
IL-12 - secreted by DCs and macs; produced in response to TLRs; stimulants IFNgamma by NK cells and T cells; host resistance against intracellular
IL-18 - enhances NK cells
IL-15 - growth stimulating and survival of NK and T cells
IL-25
IL-33
Functions of immunoglobulins
IgG – longest serum half life; functions – opsonization, complement activation, ADCC, feedback inhibition for B cells
IgE – defense against helminths, immediate hypersensitivity
IgD – naïve B cell antigen receptor
IgM – naïve B cell antigen receptor, complement activation
IgA – mucosal immunity
Classes of dendritic cells
Classical – CD11 b (drives CD4 response) and CD8 (in lymphoid tissues) or CD103 (peripheral tissues) which is involved in cross-presentation
Plasmacytoid DCs – primarily function in viral infections, when they secrete type I IFN and play role in Ag presentation
Cytoplasmic tyrosine containing motifs on signaling proteins of immune receptors
ITAMs - involved in cell activation
ITIMs - inhibit cellular response
Co-receptors for T vs B cells
T cells - CD4 and CD8
B cells CR2/CD21
Inhibitory receptors for T vs B cells
T cells - CTLA-4, PD-1
B cells - CD22, FcyRIIB (contains an ITIM motif)
Co-stimulatory signals for T cells
CD28 on the T cell - binds CD80/86 (aka B7-1/2) expressed on activated APCs
CD80/86 expression is induced by TLRs and IFNgamma
CD4 ehnances expression of CD80/86 by CD40-dependent pathway
Tregs are dependent on CD80/86:CD28 mediated co-stimulation
CD28 signaling amplifies signals induced downstream of the TCR and amplifies the NF-kB pathway
PI3K is recruited to the CD28 tail —> activates Akt and Itk as well as PLCy
Net result of CD28:B7 costim is increased expression of anti-apoptosis Bcl-2 and Bcl-XL promoting T cell survival, IL-2 production
OTHER COSTIM:
CD40L on T cells and CD40 on APCs (B cells, macs, DCs)
CD40L activates APCs to make them more potent by enhancing B7 expression and IL-12 secretion (IL-12 promotes T cell differentiation)
Ligation of the TCR by MHC-peptide ligands causes
Phosphorylation of ITAMs linked to CD3 or delta chains
Transcription factors activated by TCR signaling
NFAT - required for expression of genes encoding IL-2, IL-4, TNF; activated by calcium-calmodulin
AP-1 - transcription factor composed of FOS and Jun
NF-kB - TF activated in response to cytokine synthesis; important for TLR and cytokines
Also miRNAs - small non-coding RNAs that are transcribed from DNA but not translated – inhibit expression of genes (Argonaute proteins assoc w miRNA to form RISC)
Cytokines
IL-2 = growth, survival, and differentiation cytokines for T cells (promotes proliferation and differentiation of CD8 T cells into CTLs); activates JAK/STAT, induces anti-apop Bcl-2, stims cell cycle progression through degradation of p27
IL-17 = most important cytokines for maintenance of memory CD4 and CD8 T cells (CD127 is IL-17 receptor on Tmem cells)
IL-15 = also important for CD8 memory/survival of memory cells; produced by many cell types including DCs
IL-12 = causes differentiation of Th0 cells to Th1 cells; produced by DC pop during innate immune response
IL-4 = causes differentiation of Th0 cells to Th2 cells; involved in allergic rxns and response to helminths
IL-5 = involved in allergic rxns and response to helminths
IL-13 = involved in allergic rxns and response to helminths
IL-1 = promotes differentiation of Th0 cells to Th17 cells
IL-17 = produced by Th17 cells, interacts with macrophages
IL-22 = interacts with macrophages
IL-6 = promotes differentiation of Th0 cells to Th17 cells
TGF-beta = promotes differentiation of Th0 cells to Th17 cells
IFNgamma = secreted by CD8 T cells and Th1 cells; activates macrophages, tells B cells to switch to IgG, stims expression of proteins that enhance MHC Ag presentation
Type I IFN - stimulates differentiation to cytotoxic T cells; produced by CD pop during innate immune response
IL-21 = plays a role in induction of CD8 memory and prevention of exhaustion; produced by activated CD4 cells; contributes to generation of plasma cells, facilitates B cell selection events and B cell differentiation
B cell activation is facilitated by
CR2/CD21 receptor on B cells
C3d complement fragment is recognized by CR2 —> enhances strength of BCR signaling
What stimulates B cell proliferation
NF-kB and AP-1 (activated by CD40:CD40L signaling cascade)
Heavy chain isotope (class) switching
Regulated by cytokines produced by T helper cells
• IFNy —> B cells switch to IgG
• IL-4 —> B cell switches to IgE
• TGF-beta, BAFF, and APRIL —> B cell switches to IgA at mucosal sites
CD40 signals work w cytokines to induce switch
