KEGG PATHWAY: hsa04934

PATHWAY: hsa04934

Entry

hsa04934                    Pathway

Name

Cushing syndrome - Homo sapiens (human)

Description

Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).

Class

Human Diseases; Endocrine and metabolic disease

Pathway map

hsa04934

Cushing syndrome

Network

Element

N00290

Mutation-inactivated MEN1 to transcription

N00315

Mutation-inactivated AIP to AhR-mediated transcription

N00316

Mutation-inactivated CDKN1B to p27-cell cycle G1/S

N00319

Mutation-activated USP8 to EGFR-ERK-ACTH signaling pathway

N00320

Mutation-activated PRKACA to ACTH-cortisol signaling pathway

N00321

Mutation-activated GNAS to ACTH-cortisol signaling pathway

N00322

Mutation-inactivated PRKAR1A to ACTH-cortisol signaling pathway

N00323

Mutation-inactivated PDE11A/PDE8B to ACTH-cortisol signaling pathway

N00325

Mutation-inactivated RASD1 to CRHR-PKA-ACTH signaling pathway

N00326

Mutation-activated GNAS to CRHR-PKA-ACTH signaling pathway

N00327

Mutation-inactivated PRKAR1A to CRHR-PKA-ACTH signaling pathway

Disease

H01431

Cushing syndrome

Drug

D00420

Mitotane (JAN/USP/INN)

D01180

Trilostane (JAN/USAN)

D10950

Levoketoconazole (USAN/INN)

Organism

Homo sapiens (human) [GN:hsa]

Gene

1392	CRH; corticotropin releasing hormone [KO:K05256]

1394	CRHR1; corticotropin releasing hormone receptor 1 [KO:K04578]

1395	CRHR2; corticotropin releasing hormone receptor 2 [KO:K04579]

2778	GNAS; GNAS complex locus [KO:K04632]

107	ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]

108	ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]

109	ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]

196883

ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]

111	ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]

112	ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]

113	ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]

114	ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]

115	ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]

5566	PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]

5567	PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]

5568	PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]

1385	CREB1; cAMP responsive element binding protein 1 [KO:K05870]

1386	ATF2; activating transcription factor 2 [KO:K04450]

468	ATF4; activating transcription factor 4 [KO:K04374]

10488

CREB3; cAMP responsive element binding protein 3 [KO:K09048]

90993

CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]

64764

CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]

84699

CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]

148327

CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]

9586	CREB5; cAMP responsive element binding protein 5 [KO:K09047]

1388	ATF6B; activating transcription factor 6 beta [KO:K09049]

4221	MEN1; menin 1 [KO:K14970]

9070	ASH2L; ASH2 like, histone lysine methyltransferase complex subunit [KO:K14964]

5929	RBBP5; RB binding protein 5, histone lysine methyltransferase complex subunit [KO:K14961]

11091

WDR5; WD repeat domain 5 [KO:K14963]

54554

WDR5B; WD repeat domain 5B [KO:K14963]

4297	KMT2A; lysine methyltransferase 2A [KO:K09186] [EC:2.1.1.354]

8085	KMT2D; lysine methyltransferase 2D [KO:K09187] [EC:2.1.1.354]

1031	CDKN2C; cyclin dependent kinase inhibitor 2C [KO:K06622]

1030	CDKN2B; cyclin dependent kinase inhibitor 2B [KO:K04685]

1029	CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]

1019	CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]

1021	CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]

595	CCND1; cyclin D1 [KO:K04503]

5925	RB1; RB transcriptional corepressor 1 [KO:K06618]

1869	E2F1; E2F transcription factor 1 [KO:K17454]

1870	E2F2; E2F transcription factor 2 [KO:K09389]

1871	E2F3; E2F transcription factor 3 [KO:K06620]

51655

RASD1; ras related dexamethasone induced 1 [KO:K07843]

2770	GNAI1; G protein subunit alpha i1 [KO:K04630]

2773	GNAI3; G protein subunit alpha i3 [KO:K04630]

2771	GNAI2; G protein subunit alpha i2 [KO:K04630]

196	AHR; aryl hydrocarbon receptor [KO:K09093]

23746

AIPL1; aryl hydrocarbon receptor interacting protein like 1 [KO:K17767]

9049	AIP; aryl hydrocarbon receptor interacting protein [KO:K17767]

405	ARNT; aryl hydrocarbon receptor nuclear translocator [KO:K09097]

1027	CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]

1017	CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:2.7.11.22]

898	CCNE1; cyclin E1 [KO:K06626]

9134	CCNE2; cyclin E2 [KO:K06626]

1026	CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]

775	CACNA1C; calcium voltage-gated channel subunit alpha1 C [KO:K04850]

776	CACNA1D; calcium voltage-gated channel subunit alpha1 D [KO:K04851]

778	CACNA1F; calcium voltage-gated channel subunit alpha1 F [KO:K04853]

779	CACNA1S; calcium voltage-gated channel subunit alpha1 S [KO:K04857]

815	CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515] [EC:2.7.11.17]

817	CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515] [EC:2.7.11.17]

816	CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515] [EC:2.7.11.17]

818	CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515] [EC:2.7.11.17]

5906	RAP1A; RAP1A, member of RAS oncogene family [KO:K04353]

5908	RAP1B; RAP1B, member of RAS oncogene family [KO:K07836]

673	BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]

5604	MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]

5605	MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]

5594	MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

5595	MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

3164	NR4A1; nuclear receptor subfamily 4 group A member 1 [KO:K04465]

1956	EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]

9101	USP8; ubiquitin specific peptidase 8 [KO:K11839] [EC:3.4.19.12]

5443	POMC; proopiomelanocortin [KO:K05228]

4158	MC2R; melanocortin 2 receptor [KO:K04200]

56246

MRAP; melanocortin 2 receptor accessory protein [KO:K22398]

8622	PDE8B; phosphodiesterase 8B [KO:K18437] [EC:3.1.4.53]

5151	PDE8A; phosphodiesterase 8A [KO:K18437] [EC:3.1.4.53]

50940

PDE11A; phosphodiesterase 11A [KO:K13298] [EC:3.1.4.17 3.1.4.35]

2516	NR5A1; nuclear receptor subfamily 5 group A member 1 [KO:K08560]

6667	SP1; Sp1 transcription factor [KO:K04684]

5087	PBX1; PBX homeobox 1 [KO:K09355]

1584	CYP11B1; cytochrome P450 family 11 subfamily B member 1 [KO:K00497] [EC:1.14.15.4]

1586	CYP17A1; cytochrome P450 family 17 subfamily A member 1 [KO:K00512] [EC:1.14.14.19 1.14.14.32]

6770	STAR; steroidogenic acute regulatory protein [KO:K16931]

57552

NCEH1; neutral cholesterol ester hydrolase 1 [KO:K14349] [EC:3.1.1.-]

79798

ARMC5; armadillo repeat containing 5 [KO:K22499]

183	AGT; angiotensinogen [KO:K09821]

185	AGTR1; angiotensin II receptor type 1 [KO:K04166]

2776	GNAQ; G protein subunit alpha q [KO:K04634]

2767	GNA11; G protein subunit alpha 11 [KO:K04635]

23236

PLCB1; phospholipase C beta 1 [KO:K05858] [EC:3.1.4.11]

5330	PLCB2; phospholipase C beta 2 [KO:K05858] [EC:3.1.4.11]

5331	PLCB3; phospholipase C beta 3 [KO:K05858] [EC:3.1.4.11]

5332	PLCB4; phospholipase C beta 4 [KO:K05858] [EC:3.1.4.11]

3708	ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]

3709	ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]

3710	ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]

3776	KCNK2; potassium two pore domain channel subfamily K member 2 [KO:K04913]

8913	CACNA1G; calcium voltage-gated channel subunit alpha1 G [KO:K04854]

8912	CACNA1H; calcium voltage-gated channel subunit alpha1 H [KO:K04855]

8911	CACNA1I; calcium voltage-gated channel subunit alpha1 I [KO:K04856]

84876

ORAI1; ORAI calcium release-activated calcium modulator 1 [KO:K16056]

3739	KCNA4; potassium voltage-gated channel subfamily A member 4 [KO:K04877]

3777	KCNK3; potassium two pore domain channel subfamily K member 3 [KO:K04914]

3949	LDLR; low density lipoprotein receptor [KO:K12473]

949	SCARB1; scavenger receptor class B member 1 [KO:K13885]

1583	CYP11A1; cytochrome P450 family 11 subfamily A member 1 [KO:K00498] [EC:1.14.15.6]

3283	HSD3B1; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 [KO:K00070] [EC:1.1.1.145 5.3.3.1]

3284	HSD3B2; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2 [KO:K00070] [EC:1.1.1.145 5.3.3.1]

1589	CYP21A2; cytochrome P450 family 21 subfamily A member 2 [KO:K00513] [EC:1.14.14.16]

2271	FH; fumarate hydratase [KO:K01679] [EC:4.2.1.2]

7471	WNT1; Wnt family member 1 [KO:K03209]

7472	WNT2; Wnt family member 2 [KO:K00182]

7482	WNT2B; Wnt family member 2B [KO:K00182]

7473	WNT3; Wnt family member 3 [KO:K00312]

89780

WNT3A; Wnt family member 3A [KO:K00312]

54361

WNT4; Wnt family member 4 [KO:K00408]

7474	WNT5A; Wnt family member 5A [KO:K00444]

81029

WNT5B; Wnt family member 5B [KO:K00444]

7475	WNT6; Wnt family member 6 [KO:K00445]

7476	WNT7A; Wnt family member 7A [KO:K00572]

7477	WNT7B; Wnt family member 7B [KO:K00572]

7478	WNT8A; Wnt family member 8A [KO:K00714]

7479	WNT8B; Wnt family member 8B [KO:K00714]

7483	WNT9A; Wnt family member 9A [KO:K01064]

7484	WNT9B; Wnt family member 9B [KO:K01064]

7480	WNT10B; Wnt family member 10B [KO:K01357]

80326

WNT10A; Wnt family member 10A [KO:K01357]

7481	WNT11; Wnt family member 11 [KO:K01384]

51384

WNT16; Wnt family member 16 [KO:K01558]

8321	FZD1; frizzled class receptor 1 [KO:K02432]

8324	FZD7; frizzled class receptor 7 [KO:K02432]

2535	FZD2; frizzled class receptor 2 [KO:K02235]

7976	FZD3; frizzled class receptor 3 [KO:K02329]

8322	FZD4; frizzled class receptor 4 [KO:K02354]

7855	FZD5; frizzled class receptor 5 [KO:K02375]

8325	FZD8; frizzled class receptor 8 [KO:K02375]

8323	FZD6; frizzled class receptor 6 [KO:K02376]

11211

FZD10; frizzled class receptor 10 [KO:K02842]

8326	FZD9; frizzled class receptor 9 [KO:K02842]

1857	DVL3; dishevelled segment polarity protein 3 [KO:K02353]

1856	DVL2; dishevelled segment polarity protein 2 [KO:K02353]

1855	DVL1; dishevelled segment polarity protein 1 [KO:K02353]

2932	GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]

8312	AXIN1; axin 1 [KO:K02157]

8313	AXIN2; axin 2 [KO:K04385]

1499	CTNNB1; catenin beta 1 [KO:K02105]

324	APC; APC regulator of WNT signaling pathway [KO:K02085]

10297

APC2; APC regulator of WNT signaling pathway 2 [KO:K02085]

6932	TCF7; transcription factor 7 [KO:K02620]

83439

TCF7L1; transcription factor 7 like 1 [KO:K04490]

6934	TCF7L2; transcription factor 7 like 2 [KO:K04491]

51176

LEF1; lymphoid enhancer binding factor 1 [KO:K04492]

Compound

C00020

AMP

C00076

Calcium cation

C00187

Cholesterol

C00238

Potassium cation

C00410

Progesterone

C00575

3',5'-Cyclic AMP

C00735

Cortisol

C01176

17alpha-Hydroxyprogesterone

C01245

D-myo-Inositol 1,4,5-trisphosphate

C01953

Pregnenolone

C05138

17alpha-Hydroxypregnenolone

C05488

11-Deoxycortisol

C07557

2,3,7,8-Tetrachlorodibenzodioxin

Reference

PMID:26004339

Authors

Lacroix A, Feelders RA, Stratakis CA, Nieman LK

Title

Cushing's syndrome.

Journal

Lancet 386:913-27 (2015)
DOI:10.1016/S0140-6736(14)61375-1

Reference

PMID:27588171

Authors

Xiong Q, Ge W

Title

Gene mutations in Cushing's disease.

Journal

Biomed Rep 5:277-282 (2016)
DOI:10.3892/br.2016.729

Reference

PMID:25877147

Authors

Fukuoka H, Takahashi Y

Title

The role of genetic and epigenetic changes in pituitary tumorigenesis.

Journal

Neurol Med Chir (Tokyo) 54 Suppl 3:943-57 (2014)
DOI:10.2176/nmc.suppl.2014-3

Reference

PMID:18987159

Authors

Quereda V, Malumbres M

Title

Cell cycle control of pituitary development and disease.

Journal

J Mol Endocrinol 42:75-86 (2009)
DOI:10.1677/JME-08-0146

Reference

PMID:27742789

Authors

Caimari F, Korbonits M

Title

Novel Genetic Causes of Pituitary Adenomas.

Journal

Clin Cancer Res 22:5030-5042 (2016)
DOI:10.1158/1078-0432.CCR-16-0452

Reference

PMID:25350067

Authors

Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P

Title

Genetic mutations in sporadic pituitary adenomas--what to screen for?

Journal

Nat Rev Endocrinol 11:43-54 (2015)
DOI:10.1038/nrendo.2014.181

Reference

PMID:27625633

Authors

Hannah-Shmouni F, Faucz FR, Stratakis CA

Title

Alterations of Phosphodiesterases in Adrenocortical Tumors.

Journal

Front Endocrinol (Lausanne) 7:111 (2016)
DOI:10.3389/fendo.2016.00111

Reference

PMID:21423242

Authors

Melmed S

Title

Pathogenesis of pituitary tumors.

Journal

Nat Rev Endocrinol 7:257-66 (2011)
DOI:10.1038/nrendo.2011.40

Reference

PMID:19407507

Authors

Daly AF, Tichomirowa MA, Beckers A

Title

Genetic, molecular and clinical features of familial isolated pituitary adenomas.

Journal

Horm Res 71 Suppl 2:116-22 (2009)
DOI:10.1159/000192448

Reference

PMID:28850717

Authors

Albani A, Theodoropoulou M, Reincke M

Title

Genetics of Cushing's disease.

Journal

Clin Endocrinol (Oxf) 88:3-12 (2018)
DOI:10.1111/cen.13457

Reference

PMID:26045561

Authors

Duan K, Hernandez KG, Mete O

Title

Clinicopathological correlates of adrenal Cushing's syndrome.

Journal

Postgrad Med J 91:331-42 (2015)
DOI:10.1136/postgradmedj-2014-202612rep

Reference

PMID:26264719

Authors

Drougat L, Espiard S, Bertherat J

Title

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Journal

Eur J Endocrinol 173:M121-31 (2015)
DOI:10.1530/EJE-15-0532

Reference

PMID:17955016

Authors

Stratakis CA, Boikos SA

Title

Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias.

Journal

Nat Clin Pract Endocrinol Metab 3:748-57 (2007)
DOI:10.1038/ncpendmet0648

Reference

PMID:19906235

Authors

Refojo D, Holsboer F

Title

CRH signaling. Molecular specificity for drug targeting in the CNS.

Journal

Ann N Y Acad Sci 1179:106-19 (2009)
DOI:10.1111/j.1749-6632.2009.04983.x

Reference

PMID:12089357

Authors

Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, Stalla GK, Holsboer F, Arzt E

Title

Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways.

Journal

Mol Endocrinol 16:1638-51 (2002)
DOI:10.1210/mend.16.7.0863

Reference

PMID:15380809

Authors

Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J

Title

Cushing's syndrome variants secondary to aberrant hormone receptors.

Journal

Trends Endocrinol Metab 15:375-82 (2004)
DOI:10.1016/j.tem.2004.08.007

Reference

PMID:25485838

Authors

Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M

Title

Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

Journal

Nat Genet 47:31-8 (2015)
DOI:10.1038/ng.3166

Reference

PMID:25930709

Authors

Kaiser UB

Title

Cushing's disease: towards precision medicine.

Journal

Cell Res 25:649-50 (2015)
DOI:10.1038/cr.2015.53

Reference

PMID:28487882

Authors

Uzilov AV, Cheesman KC, Fink MY, Newman LC, Pandya C, Lalazar Y, Hefti M, Fowkes M, Deikus G, Lau CY, Moe AS, Kinoshita Y, Kasai Y, Zweig M, Gupta A, Starcevic D, Mahajan M, Schadt EE, Post KD, Donovan MJ, Sebra R, Chen R, Geer EB

Title

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Journal

Cold Spring Harb Mol Case Stud 3:a001602 (2017)
DOI:10.1101/mcs.a001602

Reference

PMID:26285834

Authors

Huang C, Shi Y, Zhao Y

Title

USP8 mutation in Cushing's disease.

Journal

Oncotarget 6:18240-1 (2015)
DOI:10.18632/oncotarget.4856