The PTH/PTHrP-SIK3 pathway affects skeletogenesis through altered mTOR signaling

Abstract

Studies have suggested a role for the mammalian (or mechanistic) target of rapamycin (mTOR) in skeletal development and homeostasis, yet there is no evidence connecting mTOR with the key signaling pathways that regulate skeletogenesis. We identified a parathyroid hormone (PTH)/PTH-related peptide (PTHrP)-salt-inducible kinase 3 (SIK3)-mTOR signaling cascade essential for skeletogenesis. While investigating a new skeletal dysplasia caused by a homozygous mutation in the catalytic domain of SIK3, we observed decreased activity of mTOR complex 1 (mTORC1) and mTORC2 due to accumulation of DEPTOR, a negative regulator of both mTOR complexes. This SIK3 syndrome shared skeletal features with Jansen metaphyseal chondrodysplasia (JMC), a disorder caused by constitutive activation of the PTH/PTHrP receptor. JMC-derived chondrocytes showed reduced SIK3 activity, elevated DEPTOR, and decreased mTORC1 and mTORC2 activity, indicating a common mechanism of disease. The data demonstrate that SIK3 is an essential positive regulator of mTOR signaling that functions by triggering DEPTOR degradation in response to PTH/PTHrP signaling during skeletogenesis.

Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling

“…Recently, humans with homozygous Sik3 missense mutation have been reported to show a Jansen's metaphyseal chondrodysplasia-like growth plate phenotype (33). These findings are entirely consistent with our data demonstrating that PTHrP inhibits SIK3 action in the growth plate, and that homozygous Sik3 gene deletion rescues perinatal lethality in mice lacking PTHrP.…”

“…Previous studies have suggested that SIK3, a kinase expressed in growth plate chondrocytes, controls chondrocyte hypertrophy in mice and humans (30,33). PTHrP, secreted from chondrocytes near the ends of bone, acts on its receptor on proliferating chondrocytes to block their differentiation into post-proliferative hypertrophic chondrocytes, thereby allowing them to continue proliferating (4).…”

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis

“…Mucinous tumors were more likely to have CNA gain of the ARRDC gene ( P = .018) which works as a regulator of cancer growth and progression by binding to integrin beta 4, a tumor‐related antigen . Mucinous tumors were also more likely to have CNA gain of the RICTOR gene which is involved in the regulation of cell growth and survival through the mTOR and RET signaling pathways . Mucinous tumors were more likely to have CNA loss of the RASA1 gene in the MSS cohort only ( P = .0304).…”

“…23 Mucinous tumors were also more likely to have CNA gain of the RICTOR gene which is involved in the regulation of cell growth and survival through the mTOR and RET signaling pathways. [24][25][26][27][28] Mucinous tumors were more likely to have CNA loss of the RASA1 gene in the MSS cohort only (P = .0304). This gene is responsible for producing a protein that regulates the RAS/ mitogen-activated protein kinase (MAPK) signaling pathway, the protein normally works as a negative regulator of the RAS/MAPK signaling pathway meaning that it can switch-off signaling in this pathway when it is not needed.…”

Therapeutic Target Discovery Using High-Throughput Genetic Screens in Acute Myeloid Leukemia

“…In a kinase-focused sgRNA library screen (targeting 482 protein kinases with ~6 sgRNA per gene focused on the kinase domains of each candidate gene) of twenty-six cell line models (including eight AML cell lines), LKB1 was identified as a selectively essential gene in AML [ 25 ]. The authors defined that LBK1 phosphorylates its downstream effector SIK3 [ 102 ], leading to further phosphorylation and suppression of histone deacetylase HDAC4. This mechanism allows maintenance of the histone H3K27 acetylation (associate with gene expression) at the enhancer loci targeted by MEF2C, a leukemic transcription factor in AML ( Figure 3 d) [ 103 ].…”