Ask about this productRelated genes to: KIAA0999 antibody
- Gene:
- SIK3 NIH gene
- Name:
- SIK family kinase 3
- Previous symbol:
- -
- Synonyms:
- FLJ12240, L19, KIAA0999, QSK
- Chromosome:
- 11q23.3
- Locus Type:
- gene with protein product
- Date approved:
- 2009-09-04
- Date modifiied:
- 2016-04-25
Related products to: KIAA0999 antibody
Related articles to: KIAA0999 antibody
- Cancer cells depend on protein quality control pathways to survive intrinsic and microenvironmental stress. Endoplasmic reticulum (ER)-selective autophagy (ER-phagy) maintains ER homeostasis by eliminating damaged ER and misfolded protein aggregates during ER stress. How ER stress-induced ER-phagy is regulated in cancer remains poorly understood. Salt-inducible kinases SIK2 and SIK3 (SIK2/3) are serine/threonine kinases implicated in metabolic regulation and cancer cell survival, but their roles in ER stress signaling and ER-phagy have not previously been studied. Here, we show that genetic or pharmacologic inhibition of SIK2/3 induces proteotoxic stress and activates the unfolded protein response through the PERK and IRE1 pathways, with predominant engagement of PERK and its downstream effector ATF4. SIK2/3 inhibition promotes ER-phagy by upregulating the ER-phagy receptor CCPG1 in an ATF4-dependent manner and increasing autophagic flux, thereby enabling cancer cell survival under stress. Disruption of this adaptive response results in the accumulation of polyubiquitinated protein aggregates, induction of CHOP, and apoptotic cell death in ovarian cancer cells. Importantly, combined treatment with the dual SIK2/3 inhibitor GRN-300 and the autophagy inhibitor chloroquine synergistically enhanced proteotoxic stress, reduced cell viability (combination index < 0.9), and triggered CHOP-dependent apoptosis. In ovarian cancer xenograft models, GRN-300 plus chloroquine markedly suppressed tumor growth and significantly prolonged survival compared with either monotherapy. Together, these findings identify SIK2/3 as key regulators of ER stress-induced ER-phagy and reveal a targetable stress-adaptation pathway that can be exploited therapeutically in ovarian cancer. - Source: PubMed
Publication date: 2026/07/01
Lu ZhenOzyurt RumeysaBildik GamzeMao WeiqunYang HailingBast Robert - Cancer-associated cachexia is a systemic wasting syndrome with no effective therapies, and it results in millions of deaths annually. Here, we established a Drosophila model of cancer cachexia using overexpression of Hipk and constitutively active Sik3 in larval epithelial tissue. Tumor-bearing larvae had significant muscle and fat body wasting, together with elevated carbohydrates and lipolysis. Mechanistically, tumors secrete Unpaired (Upd) ligands that activate JAK/STAT signaling in corpora cardiaca cells, inducing the expression of glucagon-like hormone Adipokinetic hormone (Akh). Elevated Akh, together with the lipase Brummer (Bmm), drives this systemic metabolic reprogramming and tissue catabolism. In conclusion, this study identifies a conserved tumor-host Upd-JAK/STAT-Akh signaling axis that contributes to organ wasting. - Source: PubMed
Publication date: 2026/06/16
Yu KeweiMoroak Gurpreet SVerheyen Esther M - Salt-Inducible Kinase 3 (SIK3) has emerged as a key regulator of peripheral metabolism, however its cellular and molecular function in regulating body weight and energy metabolism, particularly in hypothalamic neurons, remains unclear and largely unexplored. Here, we demonstrate that SIK3 expression is elevated in the hypothalamus of obese mice. Inactivation of SIK3 specifically in orexigenic NPY neurons reduces food intake, increases energy expenditure, and enhances white adipose tissue browning, resulting in resistance to high-fat diet-induced obesity in mice. Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders. - Source: PubMed
Publication date: 2026/06/02
Onda Danise AnnYang Chieh-HsinGoldsmith CallenBeddows Cait ATeo Rui QiZhang LeiYuan XiaoZhuoZhu YifeiLee Man KsOvens Ashley JYu DingyiSakamoto KeiScott John WMurphy Andrew JTsumaki NoriyukiHerzog HerbertDodd Garron TLoh Kim - Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy. - Source: PubMed
Publication date: 2026/05/20
Dong HanRay ArindamRotter Lara KWang JinhuaGrabski IsabellaMewada HeemajaWang LuluHuang KunTian YeMeylan MaximeBarlow GrahamYu ChenyangRaundhal MaheshYoon Sung-HeeNakhawa ShreyaDing LiyaZhao Jean JMatulonis Ursula AForetz MarcWucherpfennig Kai WIrizarry Rafael AWein Marc NGlimcher Laurie H - Sleep disruption is an early and prevalent feature of neurodegenerative disease, commonly attributed to neuronal circuit dysfunction or cell loss. However, sleep is tightly coupled to metabolic state, raising the possibility that systemic metabolic abnormalities contribute to disease-associated sleep phenotypes. Using models of TDP-43 proteinopathy, we investigated whether peripheral metabolic dysfunction plays a causal role in sleep disruption. We show that TDP-43 expression induces a chronic, starvation-like metabolic state characterized by depletion of peripheral carbohydrate stores despite normal feeding. Restoration of sleep fails to correct these metabolic defects, whereas improving peripheral metabolic state robustly rescues sleep. A modifier screen of ~650 RNAi lines identified Salt-inducible kinase 3 (SIK3) as a potent suppressor of both sleep loss and starvation sensitivity. Transcriptomic and spatial metabolomic analyses reveal that SIK3 selectively remodels a peripheral metabolic program centered on the pentose phosphate pathway and redox-associated metabolites without globally restoring energy stores. Together, these findings identify systemic metabolic dysfunction as a key driver of sleep disruption in TDP-43 proteinopathy and highlight peripheral metabolism as a potential therapeutic entry point for sleep dysfunction in neurodegenerative disease. - Source: PubMed
Publication date: 2026/05/15
Rodriguez AnyaraLuong JennyBelfer Samuel JShcherbakova OksanaDurkin JaclynKain PinkySengupta ArjunPerlegos Alexandra EAkhtar FarheenBoehmler Daniel JJin ZhechengWeljie Aalim MBonini Nancy MKayser Matthew S