STRAP

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STRAP
Identifiers
Aliases	STRAP, MAWD, PT-WD, UNRIP, serine/threonine kinase receptor associated protein
External IDs	OMIM: 605986; MGI: 1329037; HomoloGene: 43881; GeneCards: STRAP; OMA:STRAP - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p12.3 Start 15,882,387 bp[1] End 15,903,478 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6|6 G1 Start 137,712,076 bp[2] End 137,728,930 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in secondary oocyte corpus epididymis pons tail of epididymis beta cell caput epididymis anterior pituitary embryo ventricular zone ganglionic eminence Top expressed in mandibular prominence maxillary prominence somite seminiferous tubule cumulus cell abdominal wall epiblast primitive streak hair follicle ventricular zone More reference expression data BioGPS 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 Species Human Mouse Entrez 11171 20901 Ensembl ENSG00000023734 ENSMUSG00000030224 UniProt Q9Y3F4 Q9Z1Z2 RefSeq (mRNA) NM_007178 NM_011499 RefSeq (protein) NP_009109 NP_035629 Location (UCSC) Chr 12: 15.88 – 15.9 Mb Chr 6: 137.71 – 137.73 Mb PubMed search [3] [4]
Wikidata
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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.

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.

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

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.

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.

• Mothers against decapentaplegic homolog 3,^[9]
• Mothers against decapentaplegic homolog 6,^[9]
• Mothers against decapentaplegic homolog 7,^[9]
• TGF beta receptor 1,^[9][10] and
• TGF beta receptor 2.^[9][10]