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Биомеханика

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Bioregenerative Engineering Principles and Applications - Shu Q. Liu

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156

TABLE 5.1. Characteristics of Selected Signaling Molecules*

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

Src	Avian sarcoma virus protein (ASV),	536	60	Ubiquitous	A protein tyrosine kinase that regulates cell survival,
	p60-Src, tyrosine kinase pp60c-src,				proliferation, migration, and cell–cell
	tyrosine protein kinase SRC-1,				communication
	protooncogene SRC
Grb2	Growth factor receptor-bound protein 2,	217	25	Ubiquitous	Containing a SH2 domain and two SH3 domainsa
	abundant Src homology protein				interacting with growth factor receptors, serving
					as an adaptor protein, and mediating the
					transduction of mitogenic signals, such as growth
					factors
Sos	“Son of sevenless” Drosophila homolog 1,	1333	152	Ubiquitous	A guanine nucleotide exchange factor that binds to
	SOS1 guanine nucleotide exchange				Grb2 and activates the Ras protein
	factor
Crk	v-crk sarcoma virus CT10 oncogene	304	34	Lung, kidney	An adapter protein that binds to tyrosine-
	homolog, oncogene Crk				phosphorylated proteins via interaction with
					phosphotyrosine residues, and mediating
					intracellular signal transduction
Nck	Noncatalytic region of tyrosine	377	43	Ubiquitous	An adaptor protein that transduces signals from
	kinase, NCK1, NCK α, NCK adaptor				receptor tyrosine kinases to downstream signal
	protein 1, cytoplasmic protein NCK1,				recipients, such as the Ras protein
	SH2/SH3 adaptor protein NCK α
Shc	p66, Src homology 2 domain containing	583	63	Ubiquitous	Serving as an adaptor protein that mediates the
	(SHC) transforming protein 1				activation of Ras proteins in response to
					stimulation of mitogenic factors

a Note that the SH2 domain binds tyrosine-phosphorylated sequences and the two SH3 domains bind to proline-rich regions of substrate proteins. *Based on bibliography 5.2.

TABLE 5.2. Characteristics of Selected Signaling Molecules*

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

GAP	GTPase-activating protein (GAP),	1047	116	Ubiquitous	A GTPase-activating protein that activates
	guanosine triphosphatase-activating				the GTPase of the p21 Ras protein, induces
	protein, Ras p21 protein activator 1				conversion of GTP to GDP on Ras protein,
	(RASA1), p120GAP, RasGAP				and thus suppresses Ras activity, resulting
					in inhibition of cell mitogenic activities
SHP2	SH2 containing protein tyrosine	593	68	Ubiquitous	A molecule of protein tyrosine phosphatase
	phosphatase 2, protein tyrosine				family, regulating cell proliferation and
	phosphatase nonreceptor type 11				migration
	(PTPN11), protein tyrosine
	phosphatase 2C (PTP2C), tyrosine
	phosphatase SHP2, PTP-1D, SHPTP2
Phospholipase Cγ	PLC γ1, PLC1, PLCG1, PLC148	1290	149	Ubiquitous	Catalyzing the formation of inositol

1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate, an important process for G-protein receptorand Ras-mediated cell signaling

157

158

TABLE 5.2. Continued

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

Phosphatidylinositol	PI3 kinase α, PI3K α, PIK3CA,	1068	124	Ubiquitous	Serving as catalytic subunit of PI3 kinase,
3-kinase catalytic	p110 α, PI3 kinase p110 subunit α				which is composed of a regulatory subunit
subunit α					and a catalytic subunit, inducing
					phosphorylation of phosphatidylinositol
					(PtdIns), PtdIns4P, and PtdIns(4,5)P2 on
					the 3-hydroxyl group of the inositol ring,
					regulating cell proliferation and
					differentiation, and contributing to
					development of cancers
Phosphatidylinositol	PI3K β, phosphatidylinositol-4,	1070	123	Ubiquitous	Same as PI3 kinase α
3-kinase catalytic	5-bisphosphate 3-kinase
subunit β	catalytic subunit β isoform,
	phosphoinositide 3-kinase
	catalytic β polypeptide,
	phosphatidylinositol 3-kinase
	catalytic 110-kDa β, p110-β,
	PI3-kinase p110 subunit β
Phosphatidylinositol	PI3K γ, phosphatidylinositol 3	1102	126	Heart, liver,	In addition to functions as described for
3-kinase catalytic	kinase catalytic subunit γ			skeletal	PI3 kinase α, PI3 kinase γ regulates
subunit γ	isoform, phosphatidylinositol 3			muscle,	inﬂammatory reactions
	kinase catalytic 110 kDa γ, p110 γ,			pancreas,
	PI3 kinase p110 subunit γ			leukocytes

*Based on bibliography 5.2.

PROTEIN TYROSINE KINASE-MEDIATED CELL SIGNALING [5.2]

159

Growth factors

Receptors

Cell membrane

Receptor	P	P
tyrosine kinase

Grb2/SOS

	GDP	GTP
	Raf-1	MAPKKK
ATP		ATP
ATP
ADP		ADP
ADP
	ERKK	JNKK
ATP		ATP
ADP		ADP
	ERK1/2	JNK

Nucleus membrane

	CREB, Egr-1, or Elk-1
5'	3'
3'	Cis-elements
3'	5'

Figure 5.5. Schematic representation of protein tyrosine kinase receptor-mediated cell signaling (based on bibliography 5.2).

to the MAPK family. Activated JNK/SAPKs can translocate from the cytoplasm to the cell nucleus and activate transcriptional factors c-Jun, activating transcription factor (ATF)2, and Elk1. These transcriptional factors interact with corresponding cis-elements in target genes, initiating mitogenic mRNA transcription.

It is important to note that, in addition to the stimulatory effect on transcriptional factors as described above, c-Fos activated by ERK1/2 and c-Jun activated by JNK/SAPKs

160

TABLE 5.3. Characteristics of Selected Signaling Molecules*

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

PDGF receptor β	Platelet-derived growth factor	1106	124	Blood vessel, kidney,	A cell membrane tyrosine kinase
	receptor β, PDGFRB			pancreas, bone marrow	receptor that interacts with
					platelet-derived growth factors
					and regulates cell survival,
					proliferation, differentiation, and
					migration
H-Ras	Harvey murine sarcoma virus	189	21	Lung, intestine, stomach,	A protein homologous to the
	oncogene, HRAS, RASH1,			and thyroid gland	product of transforming gene of
	HRSP, C-H-RAS				Harvey murine sarcoma virus,
					mediating mitogenic signal
					transduction, and contributing
					to carcinogenesis when
					overexpressed
K-Ras	Kirsten murine sarcoma virus 2,	189	21	Lung, liver, intestine,	A protein homologous to product
	RASK2, oncogene KRAS2, V KI			leukocytes	of transforming gene of Kirsten
	RAS2 Kirsten rat sarcoma 2 viral				murine sarcoma virus, mediating
	oncogene homolog, CK RAS, cK				mitogenic signal transduction,
	Ras protein, K Ras p21 protein,				and contributing to
	c-Kirsten Ras protein, transforming				carcinogenesis when mutated
	protein p21
Raf-1	Oncogene RAF1, c-raf, v-raf-1 murine	648	73	Widely expressed	A MAP kinase kinase kinase
	leukemia viral oncogene homolog 1				phosphorylating MEK1 and
					MEK2, which in turn
					phosphorylates the serine/
					threonine-speciﬁc protein
					kinases ERK1/2 and regulates
					cell survival, proliferation, and
					differentiation

161

MEK1	MAPK/ERK kinase 1, mitogen-	393	43	Brain, heart, lung, blood	A serine/threonine kinase serving
	activated protein kinase kinase 1			vessel, liver, kidney,	as an element for the ERK1/2
	(MAPKK1, MAP2K1, MKK1,			spleen, intestine,	signaling pathway, activating
	MAP kinase kinase 1),			thymus, skeletal	mitogen-activated protein
	dual-speciﬁcity mitogen-activated			muscle	kinases including ERK1/2, and
	protein kinase kinase 1, ERK				regulating cell survival,
	activator kinase 1, mitogen-				development, proliferation, and
	activated protein kinase (MAPK)/				differentiation
	extracellular signal-regulated
	kinase (ERK) kinase 1, MAPK/ERK
	kinase 1 (MEK1)
MEK2	MAPK/ERK kinase 2, MAP	400	44	Neutrophils	Similar to function of MEK1
	kinase/Erk kinase 2, MAP2K2,
	MKK2, MAPKK2, MAPK/ERK
	kinase 2, ERK activator kinase 2,
	mitogen-activated protein kinase
	kinase 2
MEK3	MAPK/ERK kinase 3, mitogen-	352	40	Heart, blood vessel,	Similar to function of MEK1, and
	activated protein kinase kinase 3,			lung, liver, kidney,	activating MAPK14/p38-MAPK
	MAPKK3, MAP2K3, MKK3,			spleen, pancreas.
	and protein kinase mitogen-			Intestine, thymus,
	activated kinase 3			prostate gland, ovary
MEK4	MAPK/ERK kinase 4, mitogen-	399	44	Skeletal muscle	Similar to the function of MEK1,
	activated protein kinase kinase 4,				activating MAPK8/JNK1,
	SAPK/ERK kinase 1, MAPKK4,				MAPK9/JNK2, and
	MAP2K4, MKK4, JNK-activated				MAPK14/p38
	kinase 1, and JNKK1
Extracellular	ERK1/2, mitogen-activated protein	379	44	Ubiquitous	A serine, threonine, and tyrosine
signal-regulated	3 (MAPK3), p44ERK1, p44MAPK				kinase that forms a complex
kinase1					with ERK2 and regulates cell
					survival, proliferation, and
					differentiation

162

TABLE 5.3. Continued

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

Extracellular	ERK2, mitogen-activated protein	360	42	Ubiquitous	A serine, threonine, and tyrosine
signal-regulated	kinase 1, mitogen-activated protein				kinase that forms a complex
kinase 2	kinase 2 (MAPK2), protein kinase				with ERK1 and regulates cell
	mitogen-activated 1, protein kinase				survival, proliferation, and
	mitogen-activated 2, protein				differentiation
	tyrosine kinase ERK2, p42MAPK,
	p41MAPK
c-Fos	Oncogene FOS, FOS, and v-fos FBJ	380	41	Ubiquitous	Forming heterodimeric
	murine osteosarcoma viral				transcriptional factor complexes,
	oncogene homolog				known as activating protein
					(AP)-1, with proteins of the
					c-Jun family, and regulating
					cell survival, development,
					proliferation, differentiation, and
					transformation
cAMP response	CREB, CREB1, cAMP response	341	37	Brain, heart, thymus,	A transcriptional factor belonging
element-binding	element-binding protein 1,			adrenal gland	to the leucine zipper family of
protein	transactivator protein				DNA-binding proteins, binding
					to the cAMP-responsive element
					of target genes, regulating cell
					survival, proliferation, and
					differentiation, and regulating
					hepatic gluconeogenesis
early growth	Egr-1, nerve growth factor-induced	543	58	Nervous system,	Serving as a transcriptional factor
response 1	protein A, zinc ﬁnger protein 225			cartilage, blood vessel,	that binds to mitogenic genes,
				liver, stomach,	regulating cell proliferation,
				leukocytes	differentiation, and apoptosis
Elk-1	Transforming protein elk-1	428	45	Ubiquitous	Acting as a transcriptional factor
					that is a target of ERK1/2 in the
					cell nucleus, and binding to and
					activating the serum response

element in the promoter region of the c-fos gene

MEK kinase 1	MEKK1
MEK kinase 2	MEKK2, mitogen-activated protein	620	70	Ubiquitous	Acting as a serine/threonine
	kinase kinase kinase 2				protein kinase, phosphorylating
	(MAPKKK2), MAPK/ERK				MAPK7 and MAP2K4, and
	kinase kinase 2, MEK kinase 2				regulating cell proliferation,
					differentiation, and apoptosis
MEK kinase 3	MEKK3, mitogen-activated kinase	626	71	Ubiquitous	Activating the stress-activated
	kinase kinase 3, MAP/ERK				protein kinase (SAPK) and
	kinase kinase 3, MAPKKK3,				extracellular signal-regulated
	and MAP3K3				protein kinase (ERK) pathways;
					also regulating cell development
					and growth
Rac1	Ras-related C3 botulinum toxin	192	21	Ubiquitous	Acting as a Ras superfamily
	substrate 1, ρ family small				GTPase, and regulating cell
	GTP-binding protein Rac1,				proliferation, differentiation,
	p21-Rac1				and cytoskeletal reorganization
Cdc42	Cell division cycle 42, GTP-binding	191	21	Ubiquitous	A small GTPase of the ρ
	protein, 25 kDa, G25K				subfamily, regulating cell
					development, morphology,
					polarity, migration,
					transformation, and endocytosis
p21-activated	PAK, p21/CDC42/RAC1-activated	553	62	Ubiquitous	Serving as a target for the small
protein kinase	kinase 1, p21-activated kinase 1,				GTP-binding proteins Cdc42
	serine/threonine kinase PAK 1,				and Rac; also regulating
	P65 PAK, and α PAK				cytoskeleton reorganization and

cell motility

163

164

TABLE 5.3. Continued

		Amino	Molecular
Proteins	Alternative Names	Acids	Weight (kDa)	Expression	Functions

JNK1/SAPK	c-Jun kinase 1, c-Jun N-terminal	42	48	Ubiquitous	Acting as a serine/threonine kinase
	kinase 1, JNK1 α protein kinase,	7			and key element for MAP kinase
	protein kinase JNK1, mitogen-				signaling pathways, mediating
	activated protein kinase 8				the expression of immediate–
	(MAPK8), stress-activated				early genes in response to cell
	protein kinase (SAPK)				stimulation, regulating cell
					development, proliferation,
					differentiation, migration, and
					transcription; also regulating
					UV radiationand TNF
					α-induced apoptosis
c-Jun	Jun, protooncogene c Jun, v-jun	331	36	Ubiquitous	Forming heterodimeric
	avian sarcoma virus 17 oncogene				transcriptional factor complexes,
	homolog				known as activating protein
					(AP)-1, with proteins of the
					c-Fos family; also regulating
					cell survival, development,
					proliferation, differentiation,
					and apoptosis
Activating	ATF2, cAMP response element-	505	55	Brain, uterus,	Acting as a transcriptional factor,
transcription	binding protein 2 (CREB2),			lymphocytes	forming a homodimer or
factor 2	cyclic AMP-dependent				heterodimer with c-Jun, binding
	transcription factor ATF 2				to the cAMP-responsive element
					(CRE) of target genes,
					stimulating CRE-dependent
					transcription, and serving as a

histone acetyltransferase (HAT) that acetylates histones H2B and H4 and activating transcription by modulating chromatin components

*Based on bibliography 5.2.

BIBLIOGRAPHY 165

can form heterodimers and homodimers, known as activating proteins (AP)1. AP1 serves as a transcriptional factor, which interacts with AP1-speciﬁc cis elements and regulates the expression of mitogen genes. In addition to the ERK1/2 and JNK/SAPK pathways, there are several other pathways, which transduce signals from protein tyrosine kinase receptors. These include the p38 MAPK, ERK3, ERK5, and ERK6 pathways. Although different signaling molecules are involved, these pathways follow hierarchical orders similar to the ERK1/2 and JNK/SAPK pathways. (See Table 5.3.)

After extracellular ligand signals are transduced into the cell via corresponding protein tyrosine kinase receptors, the ligand–receptor complexes are clustered and internalized via endocytosis, resulting in the formation of endosomes. Within the endosomes, the ligands are dissociated from the receptors. The dimeric receptors are also split into monomers. The receptor tyrosine kinases are dephosphorylated by phosphatases. Monomeric receptors are recycled back to the cell membrane for further use.

BIBLIOGRAPHY

5.1. Principles of Cell Signaling

Marshall MS: Ras target proteins in eukaryotic cells, FASEB J 9:1311–8, 1995.

Johnson GL, Vaillancourt RR: Sequential protein kinase reactions controlling cell growth and differentiation, Curr Opin Cell Biol 6:230–8, 1994.

Heldin CH: Protein tyrosine kinase receptor signaling overview, in Handbook of Cell Signaling, Bradshaw RA, and Dennis EA, eds, Academic Press, Amsterdam, Vol. 1, 2004, pp 391–396.

Krauss G: Biochemistry of Signal Transduction and Regulation, 3rd ed, Wiley-VCH GmbH, 2003.

Mor A, Philips MR: Compartmentalized Ras/MAPK signaling, Annu Rev Immunol (in press). Liu YC, Penninger J, Karin M: Immunity by ubiquitylation: A reversible process of modiﬁcation,

Nat Rev Immunol 5:941–52, 2005.

Massague J, Seoane J, Wotton D: Smad transcription factors, Genes Dev 19:2783–810, 2005. Songyang Z, Cantley LC: Recognition and speciﬁcity in protein tyrosine kinase-mediated signal-

ing, Trends Biochem Sci 20:470–5, 1995.

Kolch W: Coordinating ERK/MAPK signalling through scaffolds and inhibitors, Nat Rev Mol Cell Biol 6:827–37, 2005.

Chen ZJ: Ubiquitin signalling in the NF-kappaB pathway, Nat Cell Biol 7:758–65, 2005. Pasquale EB: Eph receptor signalling casts a wide net on cell behaviour, Nat Rev Mol Cell Biol

6:462–75, 2005.

Berton G, Mocsai A, Lowell CA: Src and Syk kinases: Key regulators of phagocytic cell activation, Trends Immunol 26:208–14, 2005.

Jumaa H, Hendriks RW, Reth M: B cell signaling and tumorigenesis, Annu Rev Immunol 23:415– 45, 2005.

Blobel CP: ADAMs: Key components in EGFR signalling and development, Nat Rev Mol Cell Biol 6:32–43, 2005.

5.2. Protein Tyrosine Kinase-Mediated Cell Signaling

Src

Avizienyte E, Wyke AW, Jones RJ, McLean GW, Westhoff MA, Brunton VG et al: Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signaling, Nature Cell Biol 4:632–8, 2002.

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