Chapter 1 GF's and Receptors Flashcards
Role of Growth factors
stimulate activity of genes that are required for growth and division
Non-growth activities of growth factors
migration, differentiation, synthetic capacity
What produces EGF and TGF alpha
macrophages, epithelial cells, salivary glands, keratinocytes
Receptors for EGF and TGF alpha contain what
intrinsic tyrosine kinase activity
EGFR1 (ERB-B1)
transmembrane receptor located on surface of epithelial cells
binds EGF and TGF alpha
once bound, regulates cell proliferation and differentiation
Mutations of EGFR1
can lead to lung, head, neck, breast, and brain cancers
ERB-B2 (HER2)
overexpressed in breast cancers
Epidermal growth factor (EGF) functions
mitogenic for keratinocytes and fibroblasts
stimulates keratinocyte migration
stimulates formation of granulation tissue
Functions of TGF alpha
stimulates proliferation of hepatocytes
Hepatocyte growth factor (HGF) production
aka scatter factor
produced by fibroblasts, mesenchymal cells, endothelium, and non-hepatocyte liver cells
synthesized as a precursor pro-HGF activated by serine proteases released at sites of injury
What is the receptor for HGF?
MET
has intrinsic tyrosine kinase activity
overexpressed or mutated in renal tumors and thyroid papillary carcinomas
HGF functions
enhances proliferation of hepatocytes
increases cell motility
causes tissue differentiation during development (morphogen)
enhances hepatocyte survival
Platelet-derived growth factor (PDGF) isoforms
AA, AB, BB–>always ctive
CC, DD must be activated via proteolytic cleavage
PDGF storage and release
stored in platelet granules and released when platelets are activated
PDGF production
platelets, activated macrophages, endothelium, tumors, keratinocytes
2 PDGF receptors
PDGFR alpha and beta
PDGF functions
chemotactic for neutrophils, fibroblasts, and smooth muscle cells (recruitment after injury)
activates and stimulates proliferation of fibroblasts and endothelial cells
stimulates ECM protein synthesis
Vascular endothelial growth factor (VEGF) production
mesenchymal cells
Isoforms of VEGF
A, B, C, D, and PIGF (placental growth factor)
homodimeric proteins
VEGF-A
major angiogenic factor after injury and for tumors
induces angiogenesis by promoting endothelial cell migration, proliferation, and formation of vascular lumen
VEGF-B and PIGF
important for embryological vessel development
VEGF-C/D
important for angiogenesis and lymphangiogenesis
What is the most potent inducer for VEGF production?
hypoxia via hypoxia inducible factor (HIF-1)
other inducing factors at sites of injury are PDGF and TGF-alpha
Receptors for VEGF
VEGFR-1,2,3 (RTK’s)
VEGFR-2 is found in the endothelium and is the most important for angiogenesis
When is VEGF production targeted?
cancers, macular degeneration, retinopathy of prematurity, and diabetic macular edema
anti-VEGF used in macular degeneration
What can soluble versions of VEGF lead to?
preeclampsia
VEGF functions
stimulates proliferation of fenestrated endothelial cells
increases vascular permeability
Fibroblast growth factor (FGF)
associated with heparan sulface once released into the ECM and wait there for injury to occur
FGF production
macrophages, mast cells, and endothelial cells
FGF receptor
FGFR 1-4
2 types of FGF
FGF-1: acidic
FGF-2: basic
KGF/FGF-7
also a kerinocyte
produced from fibroblasts
stimulates keratinocyte migration, proliferation, and differentiation
FGF functions
chemotactic and mitogenic for fibroblasts
stimulates angiogenesis
stimulates ECM protein synthesis for wound healing
hematopoeisis
development
TGF-beta isoforms
1,2,3, but TGF-Beta 1 is the most widespread
TGF-beta production
platelets, endothelium, mononuclear inflammatory cells, T cells, macrophages, keratinocytes, fibroblasts, smooth muscle cells
Does TGF-beta require proteolysis to become active?
yes
2 receptors of TGF-beta
TGF-beta receptor I and II
have threonine/serine kinase activity
cause activation of tumor factors called smads via phosphorylation
activated smads–>smad4 heterodimer: allows for nuclear translocation for suppression/activation of DNA
TGF-beta pleiotropic activity
can cause actions that contradict each other
TGF-beta functions
drives scar formation
wound healing
Scar formation via TGF-beta
stimulates production of collagen, fibronectin, proteoglycans, inhibit collagen degradation, increase tissue inhibitors of proteases (TIMPs)
Wound healing via TGF-beta
chemotactic for leukocytes and fibroblasts
stimulates ECM protein synthesis
suppresses acute inflammation–>limits inflammatory response
