Cell Signaling Pathways Growth Factors Flashcards
what are growth factors?
substances capable of inducing cell growth, proliferation, healing, and/or differentiation
what are the major types of growth factors? (2)
proteins and steroids
signaling of growth factors involves
binding to a cell membrane receptor and then activation of various intracellular signaling pathways
what are the major families of growth factor receptors? (3)
tyrosine kinase activity
seine/threonine kinase activity
G protein coupled receptor
nerve growth factor (NGF) signaling pathway
Binding interaction between NGF and the TrkA receptor facilitates receptor dimerization and tyrosine residue phosphorylation of the cytoplasmic tail by adjacent Trk receptors. Trk receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor. The Trk receptor complex recruits a second adaptor protein called growth factor-receptor bound protein-2 (Grb2) along with a docking protein called Grb2-associated Binder-1 (GAB1) (not shown). Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation.
TrkA
tropomyosin receptor kinase A
TrkA is a high affinity receptor involved in
neuronal differentiation and preventing cell death
survival genes
p75
neurotrophin receptor
p75 is raining expressed in early
neuronal development
promote apoptosis
EGF signaling pathway
Signaling pathways and inhibitors of EGFR. Activation of EGFR leads to homodimerization/heterodimerization, phosphorylation of specific tyrosine residues, and recruitment of several proteins at the intracellular portion of the receptors. Phospholipase Cγ (pink) and STAT transcription factors (blue) bind directly to the receptor, whereas Ras/Raf/MAPK pathway (orange) and PI3K pathway (green) need several specific adaptor molecules (yellow). PI3K can also bind directly any of the erbB partners of EGFR heterodimers. Concomitantly, the activated receptors undergo endocytosis and follow two possible routes: lysosomal degradation or importin-mediated nuclear translocation. Once in the nucleus, EGFR can either behave as a proper transcription factor (for cyclin D1 up-regulation) or as coregulator of other gene transactivators. Both pathways result in nuclear activation of genes related with cell proliferation, survival, invasion, and metastasis. Two main strategies are available for EGFR kinase inhibition: mAb and small-molecule TKIs. mAbs act extracellularly, avoiding EGFR ligands binding, whereas TKIs compete with the ATP binding to the kinase domain of the receptor. DAG, 1,2-diacylglycerol; IP3, inositol 1,3,5-triphosphate; PLCγ, phospholipase Cγ; Erk-1, extracellular signal-regulated kinase-1; Erk-2, extracellular signal-regulated kinase-2; FAK, focal adhesion kinase; PKC, protein kinase C.
TGFb subfamilies (4)
TGFb subfamily
decapentaplegic (Dpp, Drosophila) related subfamily including BMPs and growth differentiation factors
action and inhibit subfamily fourth subfamily of diverse members
BMPs
bone morphogenetic proteins
action and inhibin subfamily regulate
sex organ development
genes for many growth factors or their receptors are
proto-oncogenes
not all proto-oncogenes encode growth factors. many encode
transcription factors
how are the majority of growth factors translated?
as a pro-form and then undergo proteolytic processing steps by members of the pro protein convertase family of enzymes
how many members are there of the pro protein convertase family?
9
furin is the best studied
dr. forsake has studied — for many years
SKI-1 (important for processing with SREBP)
furin
cleaves a number of pro proteins
Turin is involved in (4)
neuronal innervation
control of juxtacrine versus paracrine signaling
cartilage breakdown
tumor metastasis
steps of synthesis of TGFb (7)
TGFb precursor
dimerization and cleavage
small latent complex
large latent complex moves from the cytosol to the ecm
stored associated with eco through binding of the RGD motif to alpha integrins
proteases cleave
TGFb is released
TGFb ligands are active as
homo or heterodimers
homo/heterodimer
two polypeptide chains linked by a single disulfide bond
ligand binds to a type 2 receptor, which will
recruit a type 1 receptor subunit
type 2 receptor is a
serine/threonine kinase
binding of the ligand results in the
phosphorylation of the recruited type 1 receptor
in the canonical or classical pathway, the type 1 receptor then phosphorylates a receptor regulated
SMAD protein
how many type 1 receptors and type 2 receptors are there in mammals?
1: 7
2: 5
the canonical or classical pathway serves to initiate a
SMAD dependent intracellular signaling cascade that activates or inhibits gene transcription
myostatin
inhibitor of muscle growth
growth factors and cytokines affecting various steps in wound healing include (6)
fibroblast migration/replication keratinocyte replication angiogenesis collagen synthesis collagense secretion monocyte chemotaxis
why do dogs lick their wounds?
their saliva is rich in TGFb which starts the wound healing process
wound healing
complex process in which skin or other tissue repairs itself after injury
the classic model of wound healing can be divided into four sequential overlapping phases:
hemostasis
inflammatory phase
proliferative phase
remodeling phase
hemostasis
within minutes post injury, platelets aggregate at the injury site to form a fibrin clot which acts to control bleeding
inflammatory phase
bacteria and debris are phagocytosed and removed from the wound site. factors are released that cause migration and division of cells involved in the proliferative phase
proliferative phase
angiogenesis, collagen deposition, granulation tissue ormation, epithelialization, and wound contraction
remodeling phase
collagen is remodeled and realigned along tension force lines and cells no longer needed are removed by apoptosis
examples of disease states which can interfere with wound healing progression (4)
diabetes
venous or arterial disease
old age
infection
diabetic ulcers
diabetic wounds do not heal quickly, sometimes don’t even realize they have a wound
hemostasis involves
platelets
inflammatory phase involves (3)
monocytes
neutrophils
macrophages
proliferative phase involves (3)
fibroblasts
endothelial cells
keratinocytes
remodeling involves
fibroblasts
BMP segnalino involves
SMADs
SMADs result in
regulation of gene expression
how is growth factor expression restricted? (2)
temporarlly and spatially
how was it shown that growth factor expression is temporally and spatially separated in craniofacial growth and development?
transgenic mice expressed the lac z gene which is regulated by a BMP4 receptor. wherever BMP4 is lac z is expressed, which stains embryos with a blue dye, which shows BMP4 expression in different regions (expressed at different times and spaces in development)
fracture healing involves
spatial and temporal restricted expression of multiple BMPs
growth factors often work in combination to achieve
complex structures of growth and differentiation
salivary gland branching morphogenesis involves multiple
growth factors expressed spatially and temporally
do all growth factors stimulate growth?
no
TNF
tumor necrosis factor
TNF mediates
death pathways (intracellular signaling events lead to change in gene expression and cell death via apoptosis
what types of therapeutic options can be placed in the periodontal defect? (4)
bone grafts
enamel matrix derivative (EMD)
platelet derived growth factor (PDGF)
platelet rich plasma (PRP)
why are these substances used to treat periodontal defects?
they’re packed with growth factors to stimulate growth
why are these substances used to treat periodontal defects?
they’re packed with growth factors to stimulate growth
BMP2 mutation
brachydactyly type A2, mutation in 3’-regulatory element suggestive of a long range regulator of transcription
BMP4 mutations (2)
microphthalmia, eye, brain, and digit developmental abnormalities
orofacial cleft, microform cleft lip and cleft palate
BMP15 mutation
ovarian dysgenesis 2, hypergonadotropic ovarian failure
BMPR, type 2 mutation
pulmonary hypertension
Loeys-Dietz syndrome
caused by a mutation in the TGF-β receptor-1 and TGF-βreceptor-2. Autosomal dominant mutation causing widely spaced eyes, cleft palate or bifid uvula, and aortic aneurysms
Camurati-Engelmann disease
autosomal dominant mutation in TGF-b1 causing progressive diaphyseal dysplasia (hyperostosis and sclerosis of diaphyses of long bones)
Colorectal cancer hereditary nonpolyposis
mutations in TGF-β receptor-2
Arrhythmogenic right ventricular dysplasia 1
mutation in TGF-β3
PDGF-beta- dermatofibrosarcoma protuberans
Due to genetic rearrangement, PDGF-beta is produced without its normal regulation giving rise to tumor formation
IGF1Rl
mutation in IGF-receptor which causes resistance to IGF-1. Leads to intrauterine growth retardation and short stature
NGF
hereditary sensory and autonomic neuropathy. Mutation causing loss of deep pain and temperature perception
inflammatory bowel disease
chronic relapsing intestinal inflammation
two kinds of inflammatory bowel disease
chrons disease
ulcerative colitis
chrons and ulcerative colitis are both classified as
autoimmune diseases
what plays a key role in chronic inflammation?
TNFa
inflammatory bowel disease treatment
monoclonal antibodies, infliximab and adalimumab, which are directed against TNFa and prevent its binding to its receptor
rheumatoid arthritis
chronic inflammation
chronic inflammation can be treated with
an antibody against TNFa or other type of inhibitor
etanercept (Enbrel)
recombinant fusion protein between the TNFa receptor and the constant region of the IgG1 antibody, which binds TNFa and prevents its cellular action
