Growth factors

Alberts et al., several places including pp 893-894, 1125-1126

Their role in growth, maintenance, and survival makes them of potential interest in clinical applications. For instance, in my field (vision) there has been an interest in transplantations (and similar interventions) in restoring visual cells after their loss (in animal models and ultimately in patients). It became apparent that control (sham) treatments sometimes prevented loss and the idea was that disruption might release growth factors. Matthew LaVail and his lab at UCSF have specialized in this. The Nishi paper below suggests that some factors were of interest for treatment of ALS (amyotropic lateral sclerosis) which brings us to the topic of some famous baseball personalities, Lou Gehrig and Cal Ripken Jr.

This lecture is a collection of stories, some unrelated, but, this late in the semester, having overlap with material covered earlier.

From earlier this semester, there is a diversity in how growth factor signalling works:
TRANSPARENCY from general signalling shows RTK's
TRANSPARENCY relates to sevenless (ras MAPK) [figure from E. Culotta and D. E. Koshland, Jr. in "Molecule of the year" (a runner up) 1993, Science 262, 1958-1961
TRANSPARENCY S. Kim, referenced in Invertebrate vision shows signalling via PLC-gamma


Also, there is some Nobel Prize work:
R. Levi-Montalcini, The nerve growth factor 35 years later, Science 237, 1154-1162, 1987
see:
J.L.Marx, The 1986 Nobel Prize for physiology and medicine, Science 234, 543-544, 1986 "discoveries of growth factors"
dimer of 13 kDa protein found in snake venom and mouse salivary gland (strangely)
made by target, nerve binds receptors and is then transorted up to cell

But there is recent evidence that this retrograde transport is not necessary for effect, F.D.Miller and D.R.Kaplan TRK makes the retrograde, (Perspectives) Science 295, 1471-1473, and B. L. MacInnis and R. B. Campenot, Retrograde support of neuronal survival without retrograde transport of nerve growth factor, Science 295, 1536-1539

Nerve growth factor is a trophic factor which maintains sympathetic nervous system and some sensory neurons
TRANSPARENCY Fig. 21-109, p. 1125 - with NGF, there is neurite outgrowth in sympathetic ganglion.
Anti NGF antibody during development eliminates sympathetic nervous system
bind to transmembrane receptors, trk = tyrosine kinase receptors related to protooncogene
Effect in sympathetic- nerves using NE (or DA)
In CNS - affect cells using ACh including thise lost in Alzheimer's and Huntington's


TRANSPARENCY Table 17-2, p. 894 lists factors, related family members, specificity and representative actions
Overall scheme:
Cytokines
Neurotrophins like NGF
Neuropoietic factors (likely you are not familiar)
Hematopoietic factors (like interleukins)
Growth factors like EGF, FGF, TGF, IGF
EGF is 53 amino acids
Notch & lin-12 have EGF repeats (outside the cell and tyrosine kinase intracellularly)
NGF from targets like glands.

Historically, found in blood clots which sounds pretty esoteric, but there is a need for healing after injury. Hence one of the best known is PDGF (platelet-derived growth factor)
TRANSPARENCY Fig. 15-48, p. 761 - ligand dimer helps to dimerize receptor
(receptor dimerization covered ealrier - Fig. 15-47, p. 760)

K.D.Kimura et al., daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans, Science 277, 8942-946, 1997
also
W.Roush, Worm longevity gene cloned (Research news), Science 277, 897-898, 1997
in non-insulin-dependent diabetes, receptor is implicated
leprechaunism from receptor loss, growth arrest at birth
a lot can be accomplished because of the C. elegans genome project, but daf-2 was in unsequenced 10% of genome
dauer phase (dauer=durable) analogous to diapause in insects
pheromone signal indicates overpopulation
daf mutants - dauer-formation defect
TRANSPARENCY shows homology between insulin receptor and DAF-2
ligand binding, transmembrane, tyrosine kinase and insulin receptor substrate-1 domains shown
like insulin receptor and IGF-I receptor
ligand binding domain is 500 amino acids and cysteine rich, 36% & 35% identy respectively
tyrosine kinase domain is 275 amino acids, 70% and 50% identity
a human diabetic insulin-resistant patient has Pro1178->Leu, just like one daf-2 mutant
another human mutant is just like daf-2(e1391), morbidly obese 14-year-old
interesting that genes are related - nematodes and humans diverged 700-800 million years ago
IRS-1 is phosphorylated to recruit SH2 domain proteins
TRANSPARENCY - signal pathway
DAF-7 is TGF-beta-like signal
AGE-1 is PI 3-kinase which is involved in PIP2 generation (coded by daf-23)

M. Inoue et al., Activating mechanism of CNTF and related cytokines, Molecular Neurobiology, 12, 195-209, 1996
CNTF = ciliary neurotrophic factor is like hematopoietic cytokines
survival of ciliary ganglion neurons
in family with leukemia inhibitory factor (LIF), oncostatin M (OSM) cardiotropin-1 (CT-1), interleukins 6 & 11 (IL-6 & IL-11)
"lesion factor" (not secreted, released from damaged cells)
TRANSPARENCY (Fig. 2) 4 alpha helix compares CNTF receptor (left) and growth hormone (GH) receptor (right)
Also used for granulocyte colony-stimulating factor (G-CSF) prolactin (PRL) and erythropoietin (EPO)
The 4-helix would be so useful and stable that it would arise by convergent evolution
TRANSPARENCY (Fig. 3) CNTF binds to CNTF-R-alpha linked to membrane by GPI (glycosyl-phosphatidyl-inositol) anchor
break to TRANSPARENCY Fig, 12-51, p. 591 - GPI
coupled with transmembrane proteins gp 130 and LIF-R
Without CNTF-R, gp 130 and LIF-R used for LIF, OSM and CT-1
Without CNTF-R, gp130 and OSM-R is OSM receptor
IL-6 uses gp130 (2) and IL-6-R-alpha
& IL-11 uses IL-11R and gp130
these have overlapping biological activities
TRANSPARENCY (Fig. 5) domains of gp 130 and LIF-R
note that STAT's go to specific response elements, HRRE=hematopoietin RE
ras pathway used too

R. Nishi, Neurotrophic factors: two are better than one (perspective) Science 265, 1052-1053, 1994
TRANSPARENCY BDNF, FGF-5, CNTF, acidic FGF, basic FGF from different locations all involved in the maintenance of motorneuron
relevance is to prevention of neurodegenerations, in this case Amyotrophic lateral sclerosis (Lou Gehrig's disease)
pmn mutant mouse (motor neuron disease model) CNTF helps rescue
wobbler mutant mouse helped by BDNF and CNTF

P.C.Maisonpierre et al., Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis, Science 277, 55-60, 1997
also
D. Hanahan, Signaling vascular morphogenesis and maintenance (Perspectives, Cell biology) Science 277, 48-50, 1997
Vasculogenesis is when blood vessels are first made
Angiogenesis is when new vessels are formed
the latter is positively important in wound healing, the female reproductive system
negatively important in tumor progression and diabetic retinopathy
TRANSPARENCY the involvement of ligands (VEGF and Ang's 1 & 2, the latter about 75 kD) and receptors VEGF-R's 1 & 2, and Tie's 1 & 2
TRANSPARENCY now show in signal diagram that Ang2 is inhibitory via Tie2

C.-H. Heldin et al., TGF-beta signalling from cell membrane to nucleus through SMAD proteins (review article) Nature 390, 465-471, 1997.
TGF-beta = transforming growth factor.
family of cytokines includes Mullerian inhibiting substance and bone morphogenetic proteins (BMPs)
TRANSPARENCY (Fig. 3)
receptor is tetramer, 2 of 2 types, extracellular cysteine rich intracellular serine threonine kinase, upon ligand binding, type 2 receptor phosphorylates type 1 receptor.
Drosophila Decapentaplegic (dpp) is like BMP, receptors are Punt, Thick veins and Saxophone, and an enhancer screen turned up Mad (mothers against dpp, these Drosophila researchers are a barrel of laughs)
C. elegans has daf-1 and daf-4 that are serine/threonine kinases, and there is a homologue to mad that they called sma (I don't know why)
Anyhow, SMAD (vertebrate homologues) is mad and sma combined, presumably a negotiated settlement between C. elegans and Drosophila researchers.
Lots of different SMADs, hence the expression "different pathway-restricted SMADs"
Smad 2 and 3 get phosphorylated and form multimer with Smad4 goes to nucleus where it may recruit another protein to activate transcription. Also there are inhibitory Smads that inhibit phosphorylation.


References:

C.-H. Heldin et al., TGF-beta signalling from cell membrane to nucleus through SMAD proteins (review article) Nature 390, 465-471, 1997.

M. Inoue et al., Activating mechanism of CNTF and related cytokines, Molecular Neurobiology, 12, 195-209, 1996

K.D.Kimura et al., daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans, Science 277, 8942-946, 1997
also
W.Roush, Worm longevity gene cloned (Research news), Science 277, 897-898, 1997

R. Levi-Montalcini, The nerve growth factor 35 years later, Science 237, 1154-1162, 1987
see:
J.L.Marx, The 1986 Nobel Prize for physiology and medicine, Science 234, 543-544, 1986 "discoveries of growth factors"

P.C.Maisonpierre et al., Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis, Science 277, 55-60, 1997
also
D. Hanahan, Signaling vascular morphogenesis and maintenance (Perspectives, Cell biology) Science 277, 48-50, 1997

R. Nishi, Neurotrophic factors: two are better than one (perspective) Science 265, 1052-1053, 1994


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