STRAP

STRAP
Identifiers
Aliases	STRAP , MAWD, PT-WD, UNRIP, serine/threonine kinase receptor associated protein
External IDs	OMIM: 605986 MGI: 1329037 HomoloGene: 43881 GeneCards: STRAP
Gene location (Human)
Chr.	Chromosome 12 (human)
End	15,903,478 bp
Gene location (Mouse)
Chr.	Chromosome 6 (mouse)
End	137,728,930 bp
RNA expression pattern
	Top expressed in
	secondary oocyte; ; corpus epididymis; ; pons; ; caput epididymis; ; anterior pituitary; ; embryo; ; ganglionic eminence; ; Brodmann area 46; ; hypothalamus; ; amniotic fluid;
	Top expressed in
	maxillary prominence; ; somite; ; seminiferous tubule; ; cumulus cell; ; abdominal wall; ; primitive streak; ; hair follicle; ; atrioventricular valve; ; ganglionic eminence; ; barrel cortex;
	More reference expression data
	n/a
Gene ontology
Molecular function	signaling receptor binding ; protein binding ; RNA binding ;
Cellular component	cytoplasm ; SMN complex ; SMN-Sm protein complex ; cytosol ; nucleus ; nucleoplasm ;
Biological process	mRNA processing ; negative regulation of transcription by RNA polymerase II ; negative regulation of epithelial cell migration ; maintenance of gastrointestinal epithelium ; negative regulation of transforming growth factor beta receptor signaling pathway ; negative regulation of epithelial to mesenchymal transition ; negative regulation of pathway-restricted SMAD protein phosphorylation ; RNA splicing ; negative regulation of epithelial cell proliferation ; spliceosomal snRNP assembly ;
	Sources:Amigo / QuickGO
Orthologs
	11171
	20901
	ENSG00000023734
	ENSMUSG00000030224
	Q9Y3F4
	Q9Z1Z2
	NM_007178
	NM_011499
	NP_009109
	NP_035629
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated December 25, 2023

Serine-threonine kinase receptor-associated protein is an enzyme that in humans is encoded by the STRAP gene.^[6]

SMAD2, encoded by the SMAD2 gene in humans, is a pivotal member of the SMAD protein family, exhibiting homology with the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. Functioning as a crucial signal transducer and transcriptional modulator, SMAD2 assumes a central role in diverse cellular processes through its mediation of the transforming growth factor (TGF)-beta signaling pathway. Its regulatory purview encompasses the orchestration of cell proliferation, apoptosis, and differentiation.

SMAD2 engages in a dynamic interplay with the STRAP (Serine-Threonine Kinase Receptor-Associated Protein) gene. This interaction is characterized by the recruitment of SMAD2 to TGF-beta receptors through its association with the SMAD anchor for receptor activation (SARA) protein. Upon stimulation by TGF-beta, SMAD2 undergoes phosphorylation by TGF-beta receptors, leading to its dissociation from SARA and subsequent association with the SMAD4 family member. This orchestrated sequence of events is crucial for the translocation of SMAD2 into the cell nucleus. Within the nucleus, SMAD2 binds to target promoters and collaborates with other cofactors to form a transcription repressor complex. This cooperative interaction underscores the intricate regulatory network in which SMAD2 participates.

SMAD2's versatility extends beyond TGF-beta signaling, as it can also be phosphorylated by activin type 1 receptor kinase, enabling its mediation of signals from activin. The existence of multiple transcript variants resulting from alternative splicing further highlights the adaptability of SMAD2 in responding to various cellular cues.

The nomenclature of SMAD proteins, including SMAD2, draws from their homology with both the Drosophila protein MAD and the C. elegans protein SMA, emphasizing their evolutionary conservation. This nomenclature finds its roots in Drosophila research, where a mutation in the MAD gene of the mother repressed the decapentaplegic gene in the embryo, providing foundational insights into the regulatory network orchestrated by SMAD2 across species.

Apoptosis

The interaction between ASK1 and STRAP is characterized by specific domains, with the C-terminal domain of ASK1 and the fourth and sixth WD40 repeats of STRAP playing crucial roles.^[7]

Cysteine residues, particularly Cys1351 and Cys1360 in ASK1, and Cys152 and Cys270 in STRAP, are identified as essential for mediating the binding between these two proteins. ASK1 is found to phosphorylate STRAP at Thr175 and Ser179, suggesting a potential regulatory role for STRAP phosphorylation in ASK1 activity.

Functional assays demonstrate that wild-type STRAP, but not specific mutants, inhibits ASK1-mediated signaling to JNK and p38 kinases. This inhibitory effect is attributed to the modulation of complex formation between ASK1 and its negative regulators, such as thioredoxin and 14-3-3, or the disruption of complex formation between ASK1 and its substrate MKK3.

Moreover, STRAP exhibits a dose-dependent suppression of H2O2-induced apoptosis through direct interaction with ASK1, underscoring its negative regulatory role in ASK1 activity within the cellular context. The study also hints at the potential involvement of STRAP in PDK1-mediated signaling, given its previously identified role as a positive regulator of PDK1.

Diseases

Conditions linked to STRAP encompass Spastic Paraplegia 8, Autosomal Dominant, and Childhood Spinal Muscular Atrophy. Its involvement extends to pathways such as Signaling by TGFB family members and TGF-beta receptor signaling activating SMADs. Noteworthy Gene Ontology (GO) annotations associated with this gene involve RNA binding and kinase activity

Early follicle development in mice

The molecular mechanisms governing the development of small, gonadotrophin-independent follicles remain poorly understood, with TGFB ligands emerging as key players. Canonical TGFB signaling relies on intracellular SMAD proteins that modulate transcription. Notably, STRAP has been recognized in various tissues as an inhibitor of the TGFB-SMAD signaling pathway. This study aimed to elucidate the expression and function of STRAP in early follicle development.

Through qPCR analysis,^[8] similar expression profiles were observed for Strap, Smad3, and Smad7 in immature ovaries from mice aged 4–16 days, encompassing diverse populations of early growing follicles. Immunofluorescence revealed co-localization of STRAP and SMAD2/3 proteins in granulosa cells of small follicles. Employing a culture model with neonatal mouse ovary fragments rich in small non-growing follicles, interventions such as Strap knockdown using siRNA and STRAP protein inhibition via immuno-neutralization led to a reduction in small, non-growing follicles. Conversely, there was an increase in the proportion and size of growing follicles, implying that inhibiting STRAP facilitates follicle activation.

Recombinant STRAP protein had no impact on small, non-growing follicles but increased the mean oocyte size of growing follicles in the neonatal ovary model and stimulated the growth of isolated preantral follicles in vitro. In summary, these findings demonstrate the expression of STRAP in the mouse ovary and its ability to modulate the development of small follicles in a stage-dependent manner.

Interactions

STRAP has been shown to interact with:

Mothers against decapentaplegic homolog 2,^[9]

The nomenclature of SMAD proteins, derived from homology with Drosophila MAD and C. elegans SMA, reflects their evolutionary conservation, rooted in Drosophila research where a MAD gene mutation in the mother repressed the decapentaplegic gene in the embryo. This underscores the fundamental role of SMAD2 in cellular regulation across species. SMAD2, encoded by the SMAD2 gene, is a key player in cellular processes, mediating the transforming growth factor (TGF)-beta signaling pathway. Interacting dynamically with the STRAP gene, SMAD2 is recruited to TGF-beta receptors through association with the SMAD anchor for receptor activation (SARA) protein. Upon TGF-beta stimulation, SMAD2 undergoes phosphorylation, dissociating from SARA and forming a complex with the SMAD4 family member, facilitating nuclear translocation. Within the nucleus, SMAD2 binds to target promoters and collaborates with cofactors to form a transcription repressor complex. This interaction underscores the intricate regulatory network governed by SMAD2. Beyond TGF-beta signaling, SMAD2's versatility is evident in its phosphorylation by activin type 1 receptor kinase, enabling mediation of signals from activin. Multiple transcript variants resulting from alternative splicing highlight the adaptability of SMAD2 in responding to diverse cellular cues.

Related Research Articles

In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance, as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.

Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways.

Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene.

SMAD4, also called SMAD family member 4, Mothers against decapentaplegic homolog 4, or DPC4 is a highly conserved protein present in all metazoans. It belongs to the SMAD family of transcription factor proteins, which act as mediators of TGF-β signal transduction. The TGFβ family of cytokines regulates critical processes during the lifecycle of metazoans, with important roles during embryo development, tissue homeostasis, regeneration, and immune regulation.

SMAD family member 6, also known as SMAD6, is a protein that in humans is encoded by the SMAD6 gene.

Mothers against decapentaplegic homolog 7 or SMAD7 is a protein that in humans is encoded by the SMAD7 gene.

R-SMADs are receptor-regulated SMADs. SMADs are transcription factors that transduce extracellular TGF-β superfamily ligand signaling from cell membrane bound TGF-β receptors into the nucleus where they activate transcription TGF-β target genes. R-SMADS are directly phosphorylated on their c-terminus by type 1 TGF-β receptors through their intracellular kinase domain, leading to R-SMAD activation.

Smads comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA and MAD family of genes in Drosophila.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase encoded by the BMPR2 gene. It binds bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signaling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which the type II receptor phosphorylates. The type I receptor phosphorylates an R-SMAD, a transcriptional regulator.

The activin A receptor also known as ACVR1C or ALK-7 is a protein that in humans is encoded by the ACVR1C gene. ACVR1C is a type I receptor for the TGFB family of signaling molecules.

Activin receptor type-1B is a protein that in humans is encoded by the ACVR1B gene.

Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2. ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to fibrodysplasia ossificans progressiva, a very rare progressive genetic disease characterized by heterotopic ossification of muscles, tendons and ligaments. It is a bone morphogenetic protein receptor, type 1.

Activin receptor type-2A is a protein that in humans is encoded by the ACVR2A gene. ACVR2A is an activin type 2 receptor.

Activin receptor type-2B is a protein that in humans is encoded by the ACVR2B gene. ACVR2B is an activin type 2 receptor.

Transforming growth factor beta receptor I is a membrane-bound TGF beta receptor protein of the TGF-beta receptor family for the TGF beta superfamily of signaling ligands. TGFBR1 is its human gene.

Transforming growth factor, beta receptor II (70/80kDa) is a TGF beta receptor. TGFBR2 is its human gene.

Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.

The upstream signaling pathway is triggered by the binding of a signaling molecule, a ligand, to a receiving molecule, a receptor. Receptors and ligands exist in many different forms, and only recognize/bond to particular molecules. Upstream extracellular signaling transduce a variety of intracellular cascades.

The transforming growth factor beta (TGFβ) receptors are a family of serine/threonine kinase receptors involved in TGF beta signaling pathway. These receptors bind growth factor and cytokine signaling proteins in the TGF-beta family such as TGFβs, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), activin and inhibin, myostatin, anti-Müllerian hormone (AMH), and NODAL.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000023734 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030224 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Seong HA, Jung H, Ha H (April 2007). "NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling". The Journal of Biological Chemistry. 282 (16): 12075–12096. doi: 10.1074/jbc.m609832200 . PMID 17314099.
↑ "Entrez Gene: STRAP serine/threonine kinase receptor associated protein".
↑ Jung H, Seong HA, Manoharan R, Ha H (January 2010). "Serine-threonine kinase receptor-associated protein inhibits apoptosis signal-regulating kinase 1 function through direct interaction". The Journal of Biological Chemistry. 285 (1): 54–70. doi: 10.1074/jbc.m109.045229 . PMC 2804202 . PMID 19880523.
↑ Sharum IB, Granados-Aparici S, Warrander FC, Tournant FP, Fenwick MA (February 2017). "Serine threonine kinase receptor associated protein regulates early follicle development in the mouse ovary". Reproduction. 153 (2): 221–231. doi:10.1530/REP-16-0612. ISSN 1470-1626. PMID 27879343.
1 2 3 4 5 6 Datta PK, Moses HL (May 2000). "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Molecular and Cellular Biology. 20 (9): 3157–3167. doi:10.1128/mcb.20.9.3157-3167.2000. PMC 85610 . PMID 10757800.
1 2 Datta PK, Chytil A, Gorska AE, Moses HL (December 1998). "Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling". The Journal of Biological Chemistry. 273 (52): 34671–34674. doi: 10.1074/jbc.273.52.34671 . PMID 9856985.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000023734 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030224 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[5] Seong HA, Jung H, Ha H (April 2007). "NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling". The Journal of Biological Chemistry. 282 (16): 12075–12096. doi: 10.1074/jbc.m609832200 . PMID 17314099.

[entrez-6] "Entrez Gene: STRAP serine/threonine kinase receptor associated protein".

[7] Jung H, Seong HA, Manoharan R, Ha H (January 2010). "Serine-threonine kinase receptor-associated protein inhibits apoptosis signal-regulating kinase 1 function through direct interaction". The Journal of Biological Chemistry. 285 (1): 54–70. doi: 10.1074/jbc.m109.045229 . PMC 2804202 . PMID 19880523.

[8] Sharum IB, Granados-Aparici S, Warrander FC, Tournant FP, Fenwick MA (February 2017). "Serine threonine kinase receptor associated protein regulates early follicle development in the mouse ovary". Reproduction. 153 (2): 221–231. doi:10.1530/REP-16-0612. ISSN 1470-1626. PMID 27879343.

[pmid10757800-9] 1 2 3 4 5 6 Datta PK, Moses HL (May 2000). "STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling". Molecular and Cellular Biology. 20 (9): 3157–3167. doi:10.1128/mcb.20.9.3157-3167.2000. PMC 85610 . PMID 10757800.

[pmid9856985-10] 1 2 Datta PK, Chytil A, Gorska AE, Moses HL (December 1998). "Identification of STRAP, a novel WD domain protein in transforming growth factor-beta signaling". The Journal of Biological Chemistry. 273 (52): 34671–34674. doi: 10.1074/jbc.273.52.34671 . PMID 9856985.

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