Endocrinology Summers

Hormones Endocrine Glands Receptors Homeostasis 2nd Messengers

Nuclear Receptors Genetic Regulation Hormone Synthesis Receptor Regulation Hypothalamo-Hypophysial Communication

Tropic Hormones Neurohypophysial Nonapeptides Thyroid Axis Steroids Adrenal Axis

Adrenal Medulla Osmotic-Pressure Balance Reproductive Endocrinology Prolactin Somatic Axis

Growth Factors Immune Factors Ca++, PO4 Homeostasis Pancreatic Hormones GI Hormones

Guts 'n Brains Brain Hormones Neurosteroids Neuropeptides Endocrine Evolution

Figures for Endocrionology text:Vertebrate Endocrinology5th Edition - David O. Norris: Read pages 143-145 for this lecture acronyms    end

XXIII. Growth Factors 		

	A. Stimulate Cell Proliferation
		1. Cell cycle: 	

			a. most growth factors act in the G1 


		2. Hormones of progression

			a. GFs that work in the G1  to speed the advance
			   of an already actively dividing cell toward S


				i. includes: EGF, TGFa, IGF1, IGF2, 


			b. some factors block progression

				i. TGFb, MIS


		3. Hormones of competency

			a. make non-dividing cells sensitive to hormones of progression


				i. cannot initiate cell division

				ii. PDGF, FGF, 


	B. Peptides which can be secreted as hormones or paracrines (juxtacrines)

		1. membrane receptors


	C. Epidermal Growth Factor Family


		1. EGF, TGFa  (transforming growth factor), amphiregulin

			a. preprohormones are also active

		2. stimulate epithelial cell proliferation, free cell growth,
		   formation of new blood vessels


	D. TGFb  Family


		1. TGFb, MIS (Müllerian inhibiting substance),
		   BMPs (bone morphogenic proteins), inhibins, activins


		2. prohibits proliferation of epithelial and immune cells

			a. TGFb arrests cell cycle in G1

			b. MIS blocks development of Müllerian duct
			   derivatives  (uterus, Fallopian tubes)


		3. also anabolic

			a. TGFb stimulates other GFs, productions of matrix (itself
			   mitogenic), blood vessels, keratinocytes, intestinal epithelium

			   
			b. BMPs are produced by bone, heart, & brain
			   promote development, stimulate osteogenesis & neurogenesis

			   
			c. inhibins/activins active in embryonic formation of notochord,
			   neural tube and segmented somites

			d. TGFb and the BMPs
			   are likely involved in tissue repair

				i. released following injury


	E. Platelet-derived Growth Factor Family

		1. PDGF 

			a. is important for chemotaxis (movement of cells),
			   proliferation of connective tissue

			b. Wound repair


		2. VEGF (vascular endothelial growth factor)


			a. produced by neural and vascular smooth muscle cells

			b. increases mitogenesis of vascular endothelium

			c. increases vascular permiability


	F. Fibroblast Growth Factor Family


		1. Acidic FGF, Basic FGF, KGF (keratinocyte growth factor),  IL1


		2. Growth promoting effects

			a. stimulates proliferation of vascular + other epithelia
			   and certain fibroblasts


		3. Differentiative Effects

			a. promotes adipocyte and neuronal differentiation


	G. Insulin Family

	
		1. IGF1 and IGF2

		
		2. growth, induced by IGF production from the liver and produced locally

			a. IGF1 stimulated by  GH, and IGF2 important for fetal growth


			
	H. Nerve Growth Factor Family


		1. NGF, BDNF (brain-derived neurotrophic factor),  NT3 (neurotrophin 3)


		2. Derived from the same preprohormone


			a. 50% sequence homology


			b. synthesized in different places


		3. maintenance, survival, neurite outgrowth (axons & dendrites),
		   differentiation of neurons


		4. CNTF (ciliary neurotrophic factor)


			a. only functionally related


			b. ciliary ganglion growth, glial differentiation


	I. Hematopoietic Growth Factors


		1. stimulate growth and proliferation of blood cells (all types)


		2. Epo, CSFs (colony stimulating factors),  ILs (interleukins)


		3. stimulate cells of  the immune system

		

	J. Besides Progression and Competency, Growth factors also
	     promote Cell Survival
	   
	   	
		1. block cell death

		

	K. Additional 2nd messenger systems for growth/survival factors: Akt, mToR


		1. Akt is part of a family of protein kinases related to PKA and PKC


			a. Akt is aka PKB, Akt1,
				& RAC-PK (PK - related to A & C)

				
			b. Akt2, Akt3

			         
		2. GF binding - RTK ® Ras & IRS1 (insulin receptor substrate 1)
			         

			a. Ras G-protein is phosphorylated by RTK  (recekptor tyrosine kinase)
			   & PDK1 (phosphoinositide-dependent kinase 1)
			
				i. Ras ®PI3-K (phosphoinositide 3 Kinase) & Raf1
				
				ii. IRS1® PI3K
				
				iii. PDK1 phosphorylates ® Ras,  PI3K, and Akt
			
			
			b. PI3-K ® Akt
			
			
		3. Akt reciprocally activates mToR (mammalian target of rapomycin)
		
			a. Rictor (rapamycin insensitive companion) or Raptor (regulatory associated protein) 
			   necessary
			
			b. mToR activates GbL and S6K1/2 (p70-S6 Kinase)
			
				i. mToRC1 = mToR + Raptor + GbL (mammalian LST8/G-protein b-subunit like protein)
						  + PRAS40 + DEPTOR
				
				ii. mToRC2 = mToR + Rictor + GbL
				    +  mSIN1(mammalian stress-activated protein kinase interacting protein 1)
		
		4. Akt activates systems that prevent cell death
		
		
			a. after osmotic or oxidative stress,
			   or withdrawl  of GFs, cytokines
			   
			   
			   	i. protects from irradiation or chemotherapy
				
				
				ii. but also plays an important role in cancer
				
				
						(1) cell survival under conditions 
						    that would normally cause elimination
							
			b. Akt inhibits forkhead transcription factors
			
				i. FhTF ® Fas ® apoptosis
			
			c. mToR stimulates protein synthesis and cell growth
			
				1. mToRC1 ® S6K1/2 ® S6 gene
				
			d. ERK advances the cell cycle: G1 ® S, and stimlates  cell proliferation