The context-dependent, combinatorial logic of BMP signaling

Klumpe, Heidi; Langley, Matthew A; Linton, Jamie; Su, Christina; Antebi, Yaron E.; Elowitz, Michael B.

doi:10.1016/j.cels.2022.03.002

Cited by 57 publications

(51 citation statements)

References 115 publications

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“…However, in the case of phase responses, the output of the system is multidimensional, and the dose curves are nonlinear, even per single input, especially in the vicinity of the transition to type 0. Given this complexity, we built upon an approach that was applied to quantify combinatorial effects in bone morphogenetic protein signaling ( 16 ). We defined “linear additivity” as PRC(a,0) + PRC(0,b) = PRC(a,b), where PRC is the phase response curve, and a and b are concentrations of two resetting agents (i.e., (a,0) is a without b and vice versa).…”

Section: Resultsmentioning

confidence: 99%

Input integration by the circadian clock exhibits nonadditivity and fold-change detection

Manella

Bolshette

Golik

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Circadian clocks are synchronized by external timing cues to align with one another and the environment. Various signaling pathways have been shown to independently reset the phase of the clock. However, in the body, circadian clocks are exposed to a multitude of potential timing cues with complex temporal dynamics, raising the question of how clocks integrate information in response to multiple signals. To investigate different modes of signal integration by the circadian clock, we used Circa-SCOPE, a method we recently developed for high-throughput phase resetting analysis. We found that simultaneous exposure to different combinations of known pharmacological resetting agents elicits a diverse range of responses. Often, the response was nonadditive and could not be readily predicted by the response to the individual signals. For instance, we observed that dexamethasone is dominant over other tested inputs. In the case of signals administered sequentially, the background levels of a signal attenuated subsequent resetting by the same signal, but not by signals acting through a different pathway. This led us to examine whether the circadian clock is sensitive to relative rather than absolute levels of the signal. Importantly, our analysis revealed the involvement of a signal-specific fold-change detection mechanism in the clock response. This mechanism likely stems from properties of the signaling pathway that are upstream to the clock. Overall, our findings elucidate modes of input integration by the circadian clock, with potential relevance to clock resetting under both physiological and pathological conditions.

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Section: Resultsmentioning

confidence: 99%

Input integration by the circadian clock exhibits nonadditivity and fold-change detection

Manella

Bolshette

Golik

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Competition between high- and low-affinity ligands for receptor binding is context dependent, influences signaling outcome and has important physiological implications [ 3 , 57 , 58 ]. Loss of BMPR2 cause a context-dependent gain-of-activity and we found that ALK2 ligands were more efficient when we knocked down BMPR2 [ 34 , 59 – 62 ].…”

Section: Discussionmentioning

confidence: 99%

FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells

et al. 2023

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Background The immunophilin FKBP12 binds to TGF-β family type I receptors, including the BMP type I receptor ALK2. FKBP12 keeps the type I receptor in an inactive state and controls signaling activity. Removal of FKBP12 with drugs such as the FKBP-ligand FK506 enhances BMP activity in various cell types. In multiple myeloma cells, activation of SMAD1/5/8 leads to apoptosis. We hypothesized that removing FKBP12 from ALK2 in myeloma cells would potentiate BMP-induced ALK2-SMAD1/5/8 activity and in consequence cell death. Methods Multiple myeloma cell lines were treated with FK506, or other FKBP-binding compounds, combined with different BMPs before analyzing SMAD1/5/8 activity and cell viability. SMAD1/5/8 activity was also investigated using a reporter cell line, INA-6 BRE-luc. To characterize the functional signaling receptor complex, we genetically manipulated receptor expression by siRNA, shRNA and CRISPR/Cas9 technology. Results FK506 potentiated BMP-induced SMAD1/5/8 activation and apoptosis in multiple myeloma cell lines. By using FKBP-binding compounds with different affinity profiles, and siRNA targeting FKBP12, we show that the FK506 effect is mediated by binding to FKBP12. Ligands that typically signal via ALK3 in myeloma cells, BMP2, BMP4, and BMP10, did not induce apoptosis in cells lacking ALK3. Notably, BMP10 competed with BMP6 and BMP9 and antagonized their activity via ALK2. However, upon addition of FK506, we saw a surprising shift in specificity, as the ALK3 ligands gained the ability to signal via ALK2 and induce apoptosis. This indicates that the receptor complex can switch from an inactive non-signaling complex (NSC) to an active one by adding FK506. This gain of activity was also seen in other cell types, indicating that the observed effects have broader relevance. BMP2, BMP4 and BMP10 depended on BMPR2 as type II receptor to signal, which contrasts with BMP6 and BMP9, that activate ALK2 more potently when BMPR2 is knocked down. Conclusions In summary, our data suggest that FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells, partly by switching an NSC into an active signaling complex. FKBP12 targeting compounds devoid of immunosuppressing activity could have potential in novel treatment strategies aiming at reducing multiple myeloma tumor load.

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“…In early development, BMP growth factors act as morphogens that carry positional information and differentially instruct cell fates 23,24,26 . The combinatorial complexity arising from the substantial number of BMP ligands and receptors has the power to encode computations for finely tuned cell-type-specific responses 32,53 . Our work suggests that the spatiotemporal coding power, robustness, and flexibility which evolved for developmental patterning is harnessed for balancing plasticity and stability of neuronal circuits in the adult mammalian brain.…”

Section: Discussionmentioning

confidence: 99%

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

Okur

Schlauri

Bitsikas

et al. 2023

Preprint

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Throughout life, neuronal networks in the mammalian neocortex maintain a balance of excitation and inhibition which is essential for neuronal computation. Deviations from a balanced state have been linked to neurodevelopmental disorders and severe disruptions result in epilepsy. To maintain balance, neuronal microcircuits composed of excitatory and inhibitory neurons sense alterations in neural activity and adjust neuronal connectivity and function. Here, we identified a signaling pathway in the adult mouse neocortex that is activated in response to elevated neuronal network activity. Over-activation of excitatory neurons is signaled to the network through the elevation of BMP2, a growth factor well-known for its role as morphogen in embryonic development. BMP2 acts on parvalbumin-expressing (PV) interneurons through the transcription factor SMAD1, which controls an array of glutamatergic synapse proteins and components of peri-neuronal nets. PV interneuron-specific impairment of BMP2-SMAD1 signaling is accompanied by a loss of PV cell glutamatergic innervation, underdeveloped peri-neuronal nets, and decreased excitability. Ultimately, this impairment of PV interneuron functional recruitment disrupts cortical excitation-inhibition balance with mice exhibiting spontaneous epileptic seizures. Our findings suggest that developmental morphogen signaling is re-purposed to stabilize cortical networks in the adult mammalian brain.

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The context-dependent, combinatorial logic of BMP signaling

Cited by 57 publications

References 115 publications

Input integration by the circadian clock exhibits nonadditivity and fold-change detection

Input integration by the circadian clock exhibits nonadditivity and fold-change detection

FKBP12 is a major regulator of ALK2 activity in multiple myeloma cells

Control of neuronal excitation-inhibition balance by BMP-SMAD1 signaling

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