Details for: SIPA1

Gene ID: 6494

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SIPA1

Ensembl ID: ENSG00000213445

Description: signal-induced proliferation-associated 1

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • secretory cell CL0000151
    CSI 13.48
    rCSI 14.06%
    PRS 70.29
  • extravillous trophoblast CL0008036
    CSI 8.69
    rCSI 10.76%
    PRS 67.42
  • stem cell CL0000034
    CSI 7.75
    rCSI 7.47%
    PRS 62.1
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 7.6
    rCSI 9.96%
    PRS 82.91
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 4.9
    rCSI 3.92%
    PRS 87.45
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 4.39
    rCSI 5.32%
    PRS 54.07
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 4.36
    rCSI 5.99%
    PRS 87.92
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 4.13
    rCSI 3.14%
    PRS 83.14
  • colon epithelial cell CL0011108
    CSI 4.08
    rCSI 4.27%
    PRS 67.3
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 4.06
    rCSI 2.91%
    PRS 83.91
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 3.3
    rCSI 2.47%
    PRS 91.45
  • plasmacytoid dendritic cell, human CL0001058
    CSI 3.25
    rCSI 2.27%
    PRS 73.31
  • granulocyte CL0000094
    CSI 3.24
    rCSI 4.95%
    PRS 79.46
  • epithelial cell of lung CL0000082
    CSI 3.22
    rCSI 2.67%
    PRS 70.36
  • mature B cell CL0000785
    CSI 3.16
    rCSI 2.74%
    PRS 80.9
  • CD8-positive, alpha-beta thymocyte CL0000811
    CSI 3.14
    rCSI 4.9%
    PRS 90.1
  • double negative thymocyte CL0002489
    CSI 3.1
    rCSI 2.16%
    PRS 81.89
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 3.02
    rCSI 1.78%
    PRS 86.7
  • pulmonary capillary endothelial cell CL4028001
    CSI 2.87
    rCSI 5.48%
    PRS 83.08
  • common myeloid progenitor CL0000049
    CSI 2.82
    rCSI 2.28%
    PRS 72.27
  • myeloid leukocyte CL0000766
    CSI 2.79
    rCSI 2.57%
    PRS 72.08
  • plasmablast CL0000980
    CSI 2.74
    rCSI 2.16%
    PRS 76.96
  • activated type II NK T cell CL0000931
    CSI 2.73
    rCSI 3.08%
    PRS 85.52
  • mature T cell CL0002419
    CSI 2.71
    rCSI 2.11%
    PRS 86.55
  • granulocyte monocyte progenitor cell CL0000557
    CSI 2.6
    rCSI 2.25%
    PRS 75.11
  • pro-B cell CL0000826
    CSI 2.53
    rCSI 2.1%
    PRS 72.89
  • kidney interstitial alternatively activated macrophage CL1000695
    CSI 2.5
    rCSI 6.52%
    PRS 70.82
  • precursor B cell CL0000817
    CSI 2.43
    rCSI 2.13%
    PRS 78.99
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 2.41
    rCSI 2.19%
    PRS 83.84
  • Kupffer cell CL0000091
    CSI 2.36
    rCSI 5.39%
    PRS 71.04
  • double-positive, alpha-beta thymocyte CL0000809
    CSI 2.25
    rCSI 2.3%
    PRS 81.75
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 2.23
    rCSI 1.49%
    PRS 86.41
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 2.23
    rCSI 1.5%
    PRS 83.59
  • bronchus fibroblast of lung CL2000093
    CSI 2.17
    rCSI 1.76%
    PRS 70.56
  • myelocyte CL0002193
    CSI 2.16
    rCSI 14.17%
    PRS 90.22
  • immature B cell CL0000816
    CSI 2.14
    rCSI 1.59%
    PRS 82.93
  • elicited macrophage CL0000861
    CSI 2.1
    rCSI 1.92%
    PRS 79.39
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 2.05
    rCSI 2.48%
    PRS 79.41
  • blood vessel endothelial cell CL0000071
    CSI 2.05
    rCSI 4.25%
    PRS 67.43
  • T follicular helper cell CL0002038
    CSI 2.03
    rCSI 1.52%
    PRS 84.37
  • class switched memory B cell CL0000972
    CSI 2
    rCSI 1.49%
    PRS 85.25
  • group 3 innate lymphoid cell CL0001071
    CSI 1.94
    rCSI 1.46%
    PRS 76.28
  • early lymphoid progenitor CL0000936
    CSI 1.94
    rCSI 1.7%
    PRS 75.83
  • cerebral cortex endothelial cell CL1001602
    CSI 1.93
    rCSI 3.33%
    PRS 60.8
  • alpha-beta T cell CL0000789
    CSI 1.93
    rCSI 2.26%
    PRS 85.39
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 1.92
    rCSI 1.48%
    PRS 72.18
  • club cell CL0000158
    CSI 1.87
    rCSI 2.74%
    PRS 65.2
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 1.85
    rCSI 5.3%
    PRS 88.56
  • T-helper 17 cell CL0000899
    CSI 1.83
    rCSI 1.45%
    PRS 89.36
  • intermediate monocyte CL0002393
    CSI 1.8
    rCSI 2.72%
    PRS 75.53
  • fallopian tube secretory epithelial cell CL4030006
    CSI 1.79
    rCSI 1.72%
    PRS 70.08
  • lung endothelial cell CL1001567
    CSI 1.77
    rCSI 4.12%
    PRS 85.37
  • CD4-positive helper T cell CL0000492
    CSI 1.72
    rCSI 1.3%
    PRS 83.59
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 1.65
    rCSI 1.49%
    PRS 67.73
  • mononuclear phagocyte CL0000113
    CSI 1.65
    rCSI 3.63%
    PRS 74.54
  • dendritic cell, human CL0001056
    CSI 1.62
    rCSI 2.49%
    PRS 79.75
  • promyelocyte CL0000836
    CSI 1.51
    rCSI 2.18%
    PRS 78.34
  • lung macrophage CL1001603
    CSI 1.45
    rCSI 3.24%
    PRS 78.39
  • common dendritic progenitor CL0001029
    CSI 1.44
    rCSI 1.81%
    PRS 80.42
  • innate lymphoid cell CL0001065
    CSI 1.43
    rCSI 2.95%
    PRS 69.91
  • duct epithelial cell CL0000068
    CSI 1.4
    rCSI 2.04%
    PRS 75.21
  • lung pericyte CL0009089
    CSI 1.39
    rCSI 3.66%
    PRS 78.81
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 1.34
    rCSI 1.61%
    PRS 87.63
  • intraepithelial lymphocyte CL0002496
    CSI 1.22
    rCSI 3.32%
    PRS 92.44
  • pulmonary artery endothelial cell CL1001568
    CSI 1.17
    rCSI 1.59%
    PRS 80.61
  • Langerhans cell CL0000453
    CSI 1.15
    rCSI 1.76%
    PRS 84.38
  • transitional stage B cell CL0000818
    CSI 1.06
    rCSI 3.46%
    PRS 90.46
  • mammary gland epithelial cell CL0002327
    CSI 0.99
    rCSI 3.46%
    PRS 80.69
  • promonocyte CL0000559
    CSI 0.91
    rCSI 1.56%
    PRS 78.18
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 0.82
    rCSI 1.39%
    PRS 85.73
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.4
    rCSI 2.01%
    PRS 82.82
  • lung microvascular endothelial cell CL2000016
    CSI 0.29
    rCSI 5.67%
    PRS 82.5
  • cytotoxic T cell CL0000910
    CSI 0.18
    rCSI 1.05%
    PRS 77.6

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Signal-induced proliferation-associated 1 ([SIPA1](/details-gene/6494)) is a protein-coding gene located on chromosome 11q13.1. The protein functions as a GTPase-activating protein (GAP) with specificity for the small GTPases Rap1 and Rap2, thereby acting as a negative regulator of their signaling pathways ([Link](https://doi.org/10.1074/jbc.272.44.28081)). This function implicates [SIPA1](/details-gene/6494) in a variety of fundamental cellular processes, including the [adaptive immune response](/details-go/GO:0002250), [cytoskeleton organization](/details-go/GO:0007010), and the negative regulation of cell adhesion and growth. Expression data reveals its significance in diverse cell types, with particularly high relevance in [secretory cell](/details-cell/CL0000151) and [extravillous trophoblast](/details-cell/CL0008036), as well as broad importance across multiple lineages of the immune system, such as monocytes and T cells. Clinically, variations in [SIPA1](/details-gene/6494) have been associated with disease, as noted in OMIM ([602180](https://omim.org/entry/602180)). ## Cellular Roles and Expression Landscape The expression profile of [SIPA1](/details-gene/6494) highlights its multifaceted role in both epithelial/secretory and immune cell biology. **Overall**, the gene demonstrates its highest significance in [secretory cell](/details-cell/CL0000151) (CSI: 13.48) and [extravillous trophoblast](/details-cell/CL0008036) (CSI: 8.69), suggesting a crucial function in specialized epithelial contexts, potentially related to morphogenesis, polarity, and invasion. Its notable presence in [stem cell](/details-cell/CL0000034) (CSI: 7.75) may indicate a role in regulating proliferation and differentiation decisions. Furthermore, [SIPA1](/details-gene/6494) is a consistently significant gene across a wide spectrum of immune cells, supporting its annotated role in the [adaptive immune system](/details-pathway/R-HSA-1280218). It is a key marker in innate immune cells like [CD14-positive, CD16-positive monocyte](/details-cell/CL0002397) (CSI: 7.60) and [granulocyte](/details-cell/CL0000094) (CSI: 3.24). In the adaptive immune system, its significance is apparent throughout T cell development and differentiation, including in [CD4-positive, alpha-beta thymocyte](/details-cell/CL0000810) (CSI: 4.90), various memory T cell subsets such as [CD8-positive, alpha-beta memory T cell, CD45RO-positive](/details-cell/CL0001203) (CSI: 4.39), and [effector CD8-positive, alpha-beta T cell](/details-cell/CL0001050) (CSI: 4.13). Its presence in [mature B cell](/details-cell/CL0000785) (CSI: 3.16) and [plasmacytoid dendritic cell, human](/details-cell/CL0001058) (CSI: 3.25) further underscores its broad involvement in immune regulation. ## Pathways and Molecular Function The primary molecular function of [SIPA1](/details-gene/6494) is its [GTPase activator activity](/details-go/GO:0005096) for Rap small GTPases ([Link](https://doi.org/10.1074/jbc.272.44.28081)). By accelerating the conversion of active Rap-GTP to inactive Rap-GDP, [SIPA1](/details-gene/6494) serves as a critical brake in the [Rap1 signalling](/details-pathway/R-HSA-392517) pathway. This mechanism underpins its involvement in several key biological processes. The Rap1 pathway is a central regulator of cell adhesion and proliferation. Consequently, [SIPA1](/details-gene/6494) is annotated in the [negative regulation of cell adhesion](/details-go/GO:0007162), [negative regulation of cell cycle](/details-go/GO:0045786), and [negative regulation of cell growth](/details-go/GO:0030308). Its role in modulating the cytoskeleton and cell polarity is reflected in its high expression in epithelial lineages and its association with [cytoskeleton organization](/details-go/GO:0007010) and [establishment of epithelial cell polarity](/details-go/GO:0090162). In the context of the immune system, Rap1 signaling is essential for integrin activation following T-cell receptor (TCR) and B-cell receptor (BCR) stimulation, a process critical for immune cell trafficking, adhesion, and synapse formation. The consistent expression of [SIPA1](/details-gene/6494) across lymphocyte populations suggests it acts as a key modulator to fine-tune the strength and duration of these immune responses. Its widespread cellular localization, including the [cytoplasm](/details-go/GO:0005737), [plasma membrane](/details-go/GO:0005886), and [nucleus](/details-go/GO:0005634), allows it to regulate Rap signaling in multiple cellular compartments. ## Research Directions The dual prominence of [SIPA1](/details-gene/6494) in both epithelial and immune cell biology presents several compelling avenues for future research. A key next step would be a comparative analysis of its expression and significance in healthy versus diseased tissues to elucidate its role in pathology. Based on its known functions, several testable hypotheses can be proposed: 1. **Role in T Cell Exhaustion:** Given its function as a negative regulator of Rap1, a key co-stimulatory signaling molecule, [SIPA1](/details-gene/6494) may contribute to T cell exhaustion in chronic disease settings like cancer. Overexpression or heightened activity of [SIPA1](/details-gene/6494) in tumor-infiltrating lymphocytes could suppress anti-tumor immunity by persistently inactivating Rap1. 2. **Function in Placental Development:** The exceptionally high significance of [SIPA1](/details-gene/6494) in [extravillous trophoblast](/details-cell/CL0008036) suggests it is a critical regulator of trophoblast invasion and uterine remodeling. Dysregulation of [SIPA1](/details-gene/6494) could impair this process, potentially contributing to pregnancy complications such as pre-eclampsia. **Experimental Approach:** To test the first hypothesis regarding T cell exhaustion, a conditional knockout of [SIPA1](/details-gene/6494) in T cells (e.g., using a Lck-Cre or CD4-Cre driver mouse model) could be employed. These mice could be challenged with a syngeneic tumor model (e.g., MC38 or B16 melanoma). The anti-tumor response, phenotype of tumor-infiltrating T cells (via flow cytometry for exhaustion markers like PD-1, TIM-3, LAG-3), and overall survival would be compared between knockout and wild-type mice. A biochemical pull-down assay for active, GTP-bound Rap1 from the isolated T cells would directly confirm if the absence of [SIPA1](/details-gene/6494) leads to sustained Rap1 activation upon stimulation. **Therapeutic Potential:** [SIPA1](/details-gene/6494) represents a potential target for immunotherapy, particularly in oncology. Its role as a negative regulator of T cell activation makes it an attractive candidate for **inhibition**. Developing small molecule inhibitors or using RNAi-based therapeutics to specifically target and reduce [SIPA1](/details-gene/6494) function within tumor-infiltrating lymphocytes could lower the activation threshold of T cells, enhance their effector functions, and synergize with existing checkpoint blockade therapies to overcome T cell exhaustion.

Genular Protein ID: 327042852

Symbol: SIPA1_HUMAN

Name: Signal-induced proliferation-associated protein 1

UniProtKB Accession Codes:

Q96FS4 O14518 O60484 O60618 Q2YD83

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 10 Ensembl 2 ExpressionAtlas 1 GO 19 Gene3D 3 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 Reactome 1 RefSeq 4 SMART 1 SMR 1 STRING 1 SUPFAM 3 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9346962

Title: Human SPA-1 product selectively expressed in lymphoid tissues is a specific GTPase-activating protein for Rap1 and Rap2.

PubMed ID: 9346962

DOI: 10.1074/jbc.272.44.28081

PubMed ID: 9651531

Title: Genomic organization and cloning of the human homologue of murine Sipa-1.

PubMed ID: 9651531

DOI: 10.1016/s0378-1119(98)00212-1

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 18220336

Title: Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis.

PubMed ID: 18220336

DOI: 10.1021/pr0705441

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 21269460

Title: Initial characterization of the human central proteome.

PubMed ID: 21269460

DOI: 10.1186/1752-0509-5-17

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

Sequence Information:

  • Length: 1042
  • Mass: 112149
  • Checksum: FB52C7231EA3B6B9
  • Sequence:
    • MPMWAGGVGS PRRGMAPAST DDLFARKLRQ PARPPLTPHT FEPRPVRGPL LRSGSDAGEA 
RPPTPASPRA RAHSHEEASR PAATSTRLFT DPLALLGLPA EEPEPAFPPV LEPRWFAHYD 
VQSLLFDWAP RSQGMGSHSE ASSGTLASAE DQAASSDLLH GAPGFVCELG GEGELGLGGP 
ASPPVPPALP NAAVSILEEP QNRTSAYSLE HADLGAGYYR KYFYGKEHQN FFGMDESLGP 
VAVSLRREEK EGSGGGTLHS YRVIVRTTQL RTLRGTISED ALPPGPPRGL SPRKLLEHVA 
PQLSPSCLRL GSASPKVPRT LLTLDEQVLS FQRKVGILYC RAGQGSEEEM YNNQEAGPAF 
MQFLTLLGDV VRLKGFESYR AQLDTKTDST GTHSLYTTYQ DHEIMFHVST MLPYTPNNQQ 
QLLRKRHIGN DIVTIVFQEP GSKPFCPTTI RSHFQHVFLV VRAHTPCTPH TTYRVAVSRT 
QDTPAFGPAL PAGGGPFAAN ADFRAFLLAK ALNGEQAAGH ARQFHAMATR TRQQYLQDLA 
TNEVTTTSLD SASRFGLPSL GGRRRAAPRG PGAELQAAGS LVWGVRAAPG ARVAAGAQAS 
GPEGIEVPCL LGISAEALVL VAPRDGRVVF NCACRDVLAW TFSEQQLDLY HGRGEAITLR 
FDGSPGQAVG EVVARLQLVS RGCETRELAL PRDGQGRLGF EVDAEGFVTH VERFTFAETA 
GLRPGARLLR VCGQTLPSLR PEAAAQLLRS APKVCVTVLP PDESGRPRRS FSELYTLSLQ 
EPSRRGAPDP VQDEVQGVTL LPTTKQLLHL CLQDGGSPPG PGDLAEERTE FLHSQNSLSP 
RSSLSDEAPV LPNTTPDLLL ATTAKPSVPS ADSETPLTQD RPGSPSGSED KGNPAPELRA 
SFLPRTLSLR NSISRIMSEA GSGTLEDEWQ AISEIASTCN TILESLSREG QPIPESGDPK 
GTPKSDAEPE PGNLSEKVSH LESMLRKLQE DLQKEKADRA ALEEEVRSLR HNNRRLQAES 
ESAATRLLLA SKQLGSPTAD LA