Cripto as a target for cancer immunotherapy

Expert Opinion on Therapeutic Targets

Volumn 9, Issue 2, 2005, Pages 383-394

  Hu, Xiu Feng ^a   Xing, Pei Xiang ^a  

^a AUSTIN RESEARCH INSTITUTE   (Australia)

Author keywords

Cancer; Cripto; Immunotherapy; Monoclonal antibody; Signal transduction

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; CANCER VACCINE; CARBOPLATIN; CISPLATIN; EPIDERMAL GROWTH FACTOR; EPIDERMAL GROWTH FACTOR RECEPTOR; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FLUOROURACIL; FREUND ADJUVANT; GLYCOSYLPHOSPHATIDYLINOSITOL; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY C13; PROTEIN CRIPTO; PROTEIN CRYPTIC; PROTEIN FRL1; SIGNAL PEPTIDE; UNCLASSIFIED DRUG;

CANCER; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER INVASION; CANCER MORTALITY; CARCINOGENESIS; CELL GROWTH; CELL INVASION; CELL MEMBRANE; CELL MOTILITY; CELL PROLIFERATION; CELL SURVIVAL; DRUG MECHANISM; EMBRYO DEVELOPMENT; EPITHELIUM; EPITHELIUM TUMOR; GROWTH REGULATION; HUMAN; MEMBRANE BINDING; MESENCHYME; METASTASIS; METASTASIS POTENTIAL; NONHUMAN; PHENOTYPE; PROTEIN ANALYSIS; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN MOTIF; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TUMOR CELL; UPREGULATION;

AMINO ACID SEQUENCE; ANIMALS; EPIDERMAL GROWTH FACTOR; HUMANS; IMMUNOTHERAPY; MEMBRANE GLYCOPROTEINS; MOLECULAR SEQUENCE DATA; NEOPLASM PROTEINS; NEOPLASMS; TUMOR MARKERS, BIOLOGICAL;

EID: 18144371250     PISSN: 14728222     EISSN: None     Source Type: Journal    
DOI: 10.1517/14728222.9.2.383     Document Type: Review

References (105)

1. FINN OJ: Cancer vaccines: between the idea and the reality. Nat. Rev. Immunol. (2003) 3(8):630-641.
2. HINODA Y, SASAKI S, ISHIDA T, IMAI K: Monoclonal antibodies as effective therapeutic agents for solid tumors. Cancer Sci. (2004) 95(8):621-625.
3. ADKINS HB, BIANCO C, SCHIFFER SG et al.: Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo. J. Clin. Invest. (2003) 112(4):575-587.
4. XING PX, HU XF, PIETERSZ GA, HOSICK HL, MCKENZIE IF: Cripto: a novel target for antibody-based cancer immunotherapy. Cancer Res. (2004) 64(11):4018-4023.
5. CICCODICOLA A, DONO R, OBICI S et al.: Molecular characterization of a gene of the 'EGF family' expressed in undifferentiated human NTERA2 teratocarcinoma cells. EMBO. J. (1989) 8(7):1987-1991.
6. NORMANNO N, BIANCO C, DE LUCA A, SALOMON DS: The role of EGF-related peptides in tumor growth. Front. Biosci. (2001) 6:D685-D707.
7. ADAMSON ED, MINCHIOTTI G, SALOMON DS: Cripto: a tumor growth factor and more. J. Cell. Physiol. (2002) 190(3):267-278.
8. GIBBS JB: Mechanism-based target identification and drug discovery in cancer research. Science (2000) 287(5460):1969-1973.
9. NISHIHARA K, TSUNEYOSHI M: Undifferentiated spindle cell carcinoma of the gallbladder: a clinicopathologic, immunohistochemical, and flow cytometric study of 11 cases. Hum. Pathol. (1993) 24(12):1298-1305.
10. FUCHS IB, LICHTENEGGER W, BUEHLER H et al.: The prognostic significance of epithelial-mesenchymal transition in breast cancer. Anti-Cancer Res. (2002) 22(6A):3415-3419.
11. GILCHRIST AJ, MEUSER R, TURCHINSKY J et al.: Cell adhesion-mediated transformation of a human SCLC cell line is associated with the development of a normal phenotype. Exp. Cell Res. (2002) 276(1):63-78.
12. XUE C, PLIETH D, VENKOV C, XU C, NEILSON EG: The gatekeeper effect of epithelial-mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res. (2003) 63(12):3386-3394.
13. NIETO MA: The snail superfamily of zinc-finger transcription factors. Nat. Rev. Mol. Cell. Biol. (2002) 3(3):155-166.
14. THIERY JP: Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer (2002) 2(6):442-454.
15. GRITSMAN K, ZHANG J, CHENG S et al.: The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell (1999) 97(1):121-132.
16. SALOMON DS, BIANCO C, DE SANTIS M: Cripto: a novel epidermal growth factor (EGF)-related peptide in mammary gland development and neoplasia. Bioessays (1999) 21(1):61-70.
17. BALDASSARRE G, TUCCI M, LEMBO G et al.: A truncated form of teratocarcinoma-derived growth factor-1 (cripto-1) mRNA expressed in human colon carcinoma cell lines and tumors. Tumour Biol. (2001) 22(5):286-293.
18. SALOMAN DS, BIANCO C, EBERT AD et al.: The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer. Endocr. Relat. Cancer (2000) 7(4):199-226.
19. MINCHIOTTI G, PARISI S, LIGUORI G et al.: Membrane-anchorage of Cripto protein by glycosylphosphatidy linositol and its distribution during early mouse development. Mech. Dev. (2000) 90(2):133-142.
20. BRANDT R, NORMANNO N, GULLICK WJ et al.: Identification and biological characterization of an epidermal growth factor-related protein: cripto-1. J. Biol. Chem. (1994) 269(25):17320-17328.
21. BIANCO C, STRIZZI L, REHMAN A et al.: A Nodal- and ALK4-independent signaling pathway activated by Cripto-1 through Glypican-1 and c-Src. Cancer Res. (2003) 63(6):1192-1197.
22. BIANCO C, KANNAN S, DE SANTIS M et al.: Cripto-1 indirectly stimulates the tyrosine phosphorylation of erb B-4 through a novel receptor. J. Biol. Chem. (1999) 274(13):8624-8629.
23. KANNAN S, DE SANTIS M, LOHMEYER M et al.: Cripto enhances the tyrosine phosphorylation of Shc and activates mitogen-activated protein kinase (MAPK) in mammary epithelial cells. J. Biol. Chem. (1997) 272(6):3330-3335.
24. EBERT AD, WECHSELBERGER C, FRANK S et al.: Cripto-1 induces phosphatidylinositol 3′-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells. Cancer Res. (1999) 59(18):4502-4505.
25. DATTA SR, BRUNET A, GREENBERG ME: Cellular survival: a play in three Akts. Genes Dev. (1999) 13(22):2905-2927.
26. CLARK AS, WEST K, STREICHER S, DENNIS PA: Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. (2002) 1(9):707-717.
27. GRAY PC, HARRISON CA, VALE W: Cripto forms a complex with activin and Type II activin receptors and can block activin signaling. Proc. Natl. Acad. Sci. USA (2003) 100(9):5193-5198.
28. CHEN YG, LUI HM, LIN SL, LEE JM, YING SY: Regulation of cell proliferation, apoptosis, and carcinogenesis by activin. Exp. Biol. Med. (Maywood) (2002) 227(2):75-87.
29. HERRINGTON EE, RAM TG, SALOMON DS et al.: Expression of epidermal growth factor-related proteins in the aged adult mouse mammary gland and their relationship to tumorigenesis. J. Cell. Physiol. (1997) 170(1):47-56.
30. KENNEY NJ, HUANG RP, JOHNSON GR et al.: Detection and location of amphiregulin and Cripto-1 expression in the developing postnatal mouse mammary gland. Mol. Reprod. Dev. (1995) 41(3):277-286.
31. SIGOVA A, RHIND N, ZAMORE PD: A single Argonaute protein mediates both transcriptional and posttranscriptional silencing in Schizosaccharomyces pombe. Genes Dev. (2004) 18(19):2359-2367.
32. QI CF, LISCIA DS, NORMANNO N et al.: Expression of transforming growth factor alpha, amphiregulin and cripto-1 in human breast carcinomas. Br. J. Cancer (1994) 69(5):903-910.
33. SAEKI T, STROMBERG K, QI CF et al.: Differential immunohistochemical detection of amphiregulin and cripto in human normal colon and colorectal tumors. Cancer Res. (1992) 52(12):3467-3473.
34. FRIESS H, YAMANAKA Y, BUCHLER M et al.: Cripto, a member of the epidermal growth factor family, is over-expressed in human pancreatic cancer and chronic pancreatitis. Int. J. Cancer (1994) 56(5):668-674.
35. ALLGAYER H, HEISS MM, SCHILDBERG FW: Prognostic factors in gastric cancer. Br. J. Surg. (1997) 84(12):1651-1664.
36. FONTANINI G, DE LAURENTIIS M, VIGNATI S et al.: Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin. Cancer Res. (1998) 4(1):241-249.
37. D'ANTONIO A, LOSITO S, PIGNATA S et al.: Transforming growth factor alpha, amphiregulin and cripto-1 are frequently expressed in advanced human ovarian carcinomas. Int. J. Oncol. (2002) 21(5):941-948.
38. WECHSELBERGER C, EBERT AD, BIANCO C et al.: Cripto-1 enhances migration and branching morphogenesis of mouse mammary epithelial cells. Exp. Cell Res. (2001) 266(1):95-105.
39. BIANCO C, ADKINS HB, WECHSELBERGER C et al.: Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Mol. Cell. Biol. (2002) 22(8):2586-2597.
40. LAPTEVA N, NIEDA M, ANDO Y et al.: Expression of renin-angiotensin system genes in immature and mature dendritic cells identified using human cDNA microarray. Biochem. Biophys. Res. Commun. (2001) 285(4):1059-1065.
41. CARPENTER MK, ROSLER ES, FISK GJ et al.: Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev. Dyn. (2004) 229(2):243-258.
42. DING J, YANG L, YAN YT et al.: Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature (1998) 395(6703):702-707.
43. XU C, LIGUORI G, PERSICO MG, ADAMSON ED: Abrogation of the Cripto gene in mouse leads to failure of postgastrulation morphogenesis and lack of differentiation of cardiomyocytes. Development (1999) 126(3):483-494.
44. XU C, LIGUORI G, ADAMSON ED, PERSICO MG: Specific arrest of cardiogenesis in cultured embryonic stem cells lacking Cripto-1. Dev. Biol. (1998) 196(2):237-247.
45. NIEMEYER CC, PERSICO MG, ADAMSON ED: Cripto: roles in mammary cell growth, survival, differentiation and transformation. Cell Death Differ. (1998) 5(5):440-449.
46. YEO C, WHITMAN M: Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol. Cell (2001) 7(5):949-957.
47. DONO R, SCALERA L, PACIFICO F et al.: The murine cripto gene: expression during mesoderm induction and early heart morphogenesis. Development (1993) 118(4):1157-1168.
48. JOHNSON SE, ROTHSTEIN JL, KNOWLES BB: Expression of epidermal growth factor family gene members in early mouse development. Dev. Dyn. (1994) 201(3):216-226.
49. HAY ED: An overview of epithelial-mesenchymal transformation. Acta Anat. (Basel) (1995) 154(1):8-20.
50. VIEBAHN C: Epithelio-mesenchymal transformation during formation of the mesoderm in the mammalian embryo. Acta Anat. (Basel) (1995) 154(1):79-97.
51. CAMUS A, TAM PP: The organizer of the gastrulating mouse embryo. Curr. Top. Dev. Biol. (1999) 45:117-153.
52. GUARINO M, MICHELI P, PALLOTTI F, GIORDANO F: Pathological relevance of epithelial and mesenchymal phenotype plasticity. Pathol. Res. Pract. (1999) 195(6):379-389.
53. THIERY JP, CHOPIN D: Epithelial cell plasticity in development and tumor progression. Cancer Metastasis Rev. (1999) 18(1):31-42.
54. KRAUS C, LIEHR T, HULSKEN J et al.: Localization of the human beta-catenin gene (CTNNB1) to 3p21: a region implicated in tumor development. Genomics (1994) 23(1):272-274.
55. BONDESTAM J, HORELLIHKUITUNEN N, HILDEN K, RITVOS O, AALTONEN J: Assignment of ACVR2 and ACVR2B the human activin receptor Type II and IIB genes to chromosome bands 2q22.2- > q23.3 and 3p22 and the human follistatin gene (FST) to chromosome 5q11.2 by FISH. Cytogenet. Cell Genet. (1999) 87(3-4):219-220.
56. HARRIS RJ, SPELLMAN MW: O-linked fucose and other post-translational modifications unique to EGF modules. Glycobiology (1993) 3(3):219-224.
57. HARRIS RJ, VAN HALBEEK H, GLUSHKA J et al.: Identification and structural analysis of the tetrasaccharide NeuAc alpha(2- > 6)Gal beta (1- > 4)GlcNAc beta(1- > 3)Fuc alpha 1- > O-linked to serine 61 of human Factor IX. Biochemistry (1993) 32(26):6539-6547.
58. NIEMEYER CC, SPENCER-DENE B, WU JX, ADAMSON ED: Preneoplastic mammary tumor markers: Cripto and Amphiregulin are overexpressed in hyperplastic stages of tumor progression in transgenic mice. Int. J. Cancer (1999) 81(4):588-591.
59. KENNEY NJ, ADKINS HB, SANICOLA M: Nodal and Cripto-1: embryonic pattern formation genes involved in mammary gland development and tumorigenesis. J. Mammary Gland Biol. Neoplasia (2004) 9(2):133-144.
60. STRIZZI L, BIANCO C, NORMANNO N et al.: Epithelial mesenchymal transition is a characteristic of hyperplasias and tumors in mammary gland from MMTV-Cripto-1 transgenic mice. J. Cell. Physiol. (2004) 201(2):266-276.
61. ROBINSON MJ, COBB MH: MitogenHactivated protein kinase pathways. Curr. Opin. Cell Biol. (1997) 9(2):180-186.
62. DE BONO JS, ROWINSKY EK: Therapeutics targeting signal transduction for patients with colorectal carcinoma. Br. Med. Bull. (2002) 64:227-254.
63. KINOSHITA N, MINSHULL J, KIRSCHNER MW: The identification of two novel ligands of the FGF receptor by a yeast screening method and their activity in Xenopus development. Cell (1995) 83(4):621-630.
64. FRAME MC: Src in cancer: deregulation and consequences for cell behaviour. Biochim. Biophys. Acta (2002) 1602(2):114-130.
65. KUMAR A, NOVOSELOV V, CELESTE AJ et al.: Nodal signaling uses activin and transforming growth factor-beta receptorHregulated Smads. J. Biol. Chem. (2001) 276(1):656-661.
66. SCHIFFER SG, FOLEY S, KAFFASHAN A et al.: Fucosylation of Cripto is required for its ability to facilitate nodal signaling. J. Biol. Chem. (2001) 276(41):37769-37778.
67. BIANCO C, NORMANNO N, DE LUCA A et al.: Detection and localization of Cripto-1 binding in mouse mammary epithelial cells and in the mouse mammary gland using an immunoglobulinHcripto-1 fusion protein. J. Cell. Physiol. (2002) 190(1):74-82.
68. GIBBS JB. Anticancer drug targets: growth factors and growth factor signaling. J. Clin. Invest. (2000) 105(1):9-13.
69. TSUKITA S, NAGAFUCHI A, YONEMURA S: Molecular linkage between cadherins and actin filaments in cell-cell adherens junctions. Curr. Opin. Cell Biol. (1992) 4(5):834-839.
70. EBERT AD, WECHSELBERGER C, NEES M et al.: Cripto-1-induced increase in vimentin expression is associated with enhanced migration of human Caski cervical carcinoma cells. Exp. Cell Res. (2000) 257(1):223-229.
71. NORMANNO N, DE LUCA A, BIANCO C et al.: Cripto-1 overexpression leads to enhanced invasiveness and resistance to anoikis in human MCF-7 breast cancer cells. J. Cell. Physiol. (2004) 198(1):31-39.
72. BEHRENS J, WEIDNER KM, FRIXEN UH et al.: The role of E-cadherin and scatter factor in tumor invasion and cell motility. Exs (1991) 59:109-126.
73. HAJRA KM, JI X, FEARON ER: Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements. Oncogene (1999) 18(51):7274-7279.
74. NIESET JE, REDFIELD AR, JIN F et al.: Characterization of the interactions of alpha-catenin with alpha-activin and betaHcatenin/plakoglobin. J. Cell Sci. (1997) 110(Pt 8):1013-1022.
75. SAVAGNER P. Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays (2001) 23(10):912-923.
76. SHIBAMOTO S, HAYAKAWA M, TAKEUCHI K et al.: Tyrosine phosphorylation of beta-catenin and plakoglobin enhanced by hepatocyte growth factor and epidermal growth factor in human carcinoma cells. Cell Adhes. Commun. (1994) 1(4):295-305.
77. MORKEL M, HUELSKEN J, WAKAMIYA M et al.: Beta-catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development (2003) 130(25):6283-6294.
78. MASSZI A, DI CIANO C, SIROKMANY G et al.: Central role for Rho in TGF-beta1Hinduced alpha-smooth muscle actin expression during epithelial-mesenchymal transition. Am. J. Physiol. Renal Physiol (2003) 284(5):F911-F924.
79. STEINERT PM, ROOP DR: Molecular and cellular biology of intermediate filaments. Ann. Rev. Biochem. (1988) 57:593-625.
80. GILLES C, POLETTE M, ZAHM JM et al.: Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci. (1999) 112(Pt 24):4615-4625.
81. BLANCO MJ, MORENO-BUENO G, SARRIO D et al.: Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene (2002) 21(20):3241-3246.
82. CANO A, PEREZ-MORENO MA, RODRIGO I et al.: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. (2000) 2(2):76-83.
83. BATLLE E, SANCHO E, FRANCI C et al.: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell Biol. (2000) 2(2):84-89.
84. ZHOU BP, DENG J, XIA W et al.: Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelialHmesenchymal transition. Nat. Cell Biol. (2004) 6(10):931-940.
85. SCHLESSINGER K, HALL A: GSK-3beta sets Snail's pace. Nat. Cell Biol. (2004) 6(10):913-915.
86. DANN CE, HSIEH JC, RATTNER A et al.: Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature (2001) 412(6842):86-90.
87. UTHOFF SM, EICHENBERGER MR, MCAULIFFE TL, HAMILTON CJ, GALANDIUK S: Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer. Mol. Carcinog. (2001) 31(1):56-62.
88. SEIDENSTICKER MJ, BEHRENS J: Biochemical interactions in the wnt pathway. Biochim. Biophys. Acta (2000) 1495(2):168-182.
89. HENDERSON BR, FAGOTTO F: The ins and outs of APC and beta-catenin nuclear transport. EMBO Rep. (2002) 3(9):834-839.
90. VAN DE WETERING M, SANCHO E, VERWEIJ C et al.: The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell (2002) 111(2):241-250.
91. MUNEMITSU S, ALBERT I, SOUZA B, RUBINFELD B, POLAKIS P: Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein. Proc. Natl. Acad. Sci. USA (1995) 92(7):3046-3050.
92. MORIN PJ, SPARKS AB, KORINEK V et al.: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science (1997) 275(5307):1787-1790.
93. MOSER AR, DOVE WF, ROTH KA, GORDON JI: The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system. J. Cell Biol. (1992) 116(6):1517-1526.
94. HYNES RO: Integrins: bidirectional, allosteric signaling machines. Cell (2002) 110(6):673-687.
95. SCHATZMANN F, MARLOW R, STREULI CH: Integrin signaling and mammary cell function. J. Mammary Gland Biol. Neoplasia (2003) 8(4):395-408.
96. MAEMURA M, AKIYAMA SK, WOODS VL, JR., DICKSON RB: Expression and ligand binding of alpha 2 beta 1 integrin on breast carcinoma cells. Clin. Exp. Metastasis (1995) 13(4):223-35.
97. SOLIC N, DAVIES DE: Differential effects of EGF and amphiregulin on adhesion molecule expression and migration of colon carcinoma cells. Exp. Cell Res. (1997) 234(2):465-476.
98. LYNCH DK, ELLIS CA, EDWARDS PA, HILES ID: Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism. Oncogene (1999) 18(56):8024-8032.
99. OLOUMI A, MCPHEE T, DEDHAR S: Regulation of E-cadherin expression and beta-catenin/Tcf transcriptional activity by the integrin-linked kinase. Biochim. Biophys. Acta (2004) 1691(1):1-15.
100. GRILLE SJ, BELLACOSA A, UPSON J et al.: The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. (2003) 63(9):2172-2178.
101. XIA Z, DICKENS M, RAINGEAUD J, DAVIS RJ, GREENBERG ME: Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science (1995) 270(5240):1326-1331.
102. AGUIRRE-GHISO JA, ESTRADA Y, LIU D, OSSOWSKI L: ERK(MAPK) activity as a determinant of tumor growth and dormancy, regulation by p38(SAPK). Cancer Res. (2003) 63(7):1684-1695.
103. NORMANNO N, BIANCO C, DAMIANO V et al.: Growth inhibition of human colon carcinoma cells by combinations of anti-epidermal growth factor-related growth factor antisense oligonucleotides. Clin. Cancer Res. (1996) 2(3):601-609.
104. NORMANNO N, DE LUCA A, MAIELLO MR et al.: CRIPTO-1: a novel target for therapeutic intervention in human carcinoma. Int. J. Oncol. (2004) 25(4):1013-1020.
105. DILLON CP, SANDY P, NENCIONI A et al.: RNAi as an Experimental and Therapeutic Tool to Study and Regulate Physiological and Disease Processes. Ann. Rev. Physiol. (2004) 67:147-173.