DegronMD - Q99743(NPAS2)

FUNCTION: Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. The NPAS2-ARNTL/BMAL1 heterodimer positively regulates the expression of MAOA, F7 and LDHA and modulates the circadian rhythm of daytime contrast sensitivity by regulating the rhythmic expression of adenylate cyclase type 1 (ADCY1) in the retina. NPAS2 plays an important role in sleep homeostasis and in maintaining circadian behaviors in normal light/dark and feeding conditions and in the effective synchronization of feeding behavior with scheduled food availability. Regulates the gene transcription of key metabolic pathways in the liver and is involved in DNA damage response by regulating several cell cycle and DNA repair genes. Controls the circadian rhythm of NR0B2 expression by binding rhythmically to its promoter (By similarity). Mediates the diurnal variation in the expression of GABARA1 receptor in the brain and contributes to the regulation of anxiety-like behaviors and GABAergic neurotransmission in the ventral striatum (By similarity). {ECO:0000250|UniProtKB:P97460, ECO:0000269|PubMed:11441146, ECO:0000269|PubMed:11441147, ECO:0000269|PubMed:14645221, ECO:0000269|PubMed:18439826, ECO:0000269|PubMed:18819933}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.P726L	TCGA-2W-A8YY	CESC	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.2778
p.P726L	DO223732	CESC	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.2778
p.N646S	TCGA-77-A5GH	LUSC	TCGA	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.3056
p.N646S	TCGA-77-A5GH	LUSC	TCGA	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.2222
p.N646S	DO45452	LUSC	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.3056
p.N646S	DO45452	LUSC	ICGC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.2222
p.V729F	TCGA-95-7039	LUAD	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.V729F	DO228974	LICA	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.V729F	DO23907	LUAD	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.M727L	TCGA-AA-3819	COAD	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.25
p.M727L	DO10590	COAD	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.25
p.A639D	TCGA-BR-8360	STAD	TCGA	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1111
p.A639D	DO47745	STAD	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1111
p.V729I	TCGA-D1-A0ZQ	UCEC	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.V729I	DO41879	UCEC	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.L730M	TCGA-EE-A2MN	SKCM	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1667
p.L730M	DO37423	SKCM	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1667
p.V711M	TCGA-FI-A2D0	UCEC	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.0833
p.V711M	DO43891	UCEC	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.0833
p.P728L	TCGA-FS-A1ZN	SKCM	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.2222
p.P728L	DO38165	SKCM	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.2222
p.P715L	TCGA-YD-A89C	SKCM	TCGA	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.P715L	DO219501	SKCM	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1944
p.S723N	DO230309	COCA	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation altering degron motif	0.7069
p.A640T	DO227802	COCA	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1389
p.A640T	DO227802	COCA	ICGC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.0556
p.Q655H	DO229035	LICA	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.2778
p.Q655H	DO229035	LICA	ICGC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.3056
p.A637S	DO229038	LICA	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.0556
p.N646H	DO48746	LIRI	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.3056
p.N646H	DO48746	LIRI	ICGC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.2222
p.M732R	DO224563	LUSC	ICGC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.1111
p.Q659H	DO51531	PACA	ICGC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1667
p.Q659H	DO51531	PACA	ICGC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.1944
p.A720T	SIDM00758	Non-Small Cell Lung Carcinoma	GDSC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation altering degron motif	0.7139
p.A720T	SIDM00400	B-Cell Non-Hodgkin's Lymphoma	GDSC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation altering degron motif	0.7139
p.A720T	SIDM00757	Non-Small Cell Lung Carcinoma	GDSC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation altering degron motif	0.7139
p.P719H	SIDM00783	Colorectal Carcinoma	GDSC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.3056
p.P719H	ACH-000971	Colon/Colorectal Cancer	CCLE	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.3056
p.P719H	HCT-116	large intestine	COSMIC	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.3056
p.A640V	SIDM01611	Endometrial Carcinoma	GDSC	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1389
p.A640V	SIDM01611	Endometrial Carcinoma	GDSC	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.0556
p.A640V	ACH-000996	Endometrial/Uterine Cancer	CCLE	LTTPAST	DEG_SCF_FBW7_1	647:653	Mutation rewiring degron network	0.1389
p.A640V	ACH-000996	Endometrial/Uterine Cancer	CCLE	PASTS	DEG_SPOP_SBC_1	650:654	Mutation rewiring degron network	0.0556
p.P728S	ACH-001392	Breast Cancer	CCLE	ANSSS	DEG_SPOP_SBC_1	720:724	Mutation rewiring degron network	0.2222

Kaplan plot for NPAS2 in

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*NOTE: the Kaplan plots were collected from OncoLnc

DegronMD: protein-targeted degradation, mutation and drug response to degrons

NPAS2

UniProt ID: Q99743

Entrez ID: 4862

Protein name: Neuronal PAS domain-containing protein 2 (Neuronal PAS2) (Basic-helix-loop-helix-PAS protein MOP4) (Class E basic helix-loop-helix protein 9) (bHLHe9) (Member of PAS protein 4) (PAS domain-containing protein 4)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for NPAS2 in