Growth Factor Modulation With TGF-β Cleavage-Site Control
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Solution Overview
Problem
There is a need for agents and methods to modulate cell signaling and cellular activities, particularly those involving TGF-β family member proteins, which are tightly regulated through interactions with other biomolecules and the extracellular matrix, and require tools for precise modulation of their signaling pathways.
Innovation Solution
Recombinant proteins and chimeric proteins comprising specific protein modules from TGF-β family members, along with antibodies that stabilize or release growth factors, are used to modulate the level of free growth factor in a cell niche, thereby controlling cellular signaling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant proteins with modified furin cleavage sites are used, then growth factor release is prevented, but signaling modulation capability is reduced
Solution Approach 1:
The prodomain is segmented into functional modules including LAP, straightjacket region, and furin cleavage site region. This segmentation allows independent manipulation of each module to achieve precise control over growth factor release while maintaining signaling modulation capability through other regions.
Solution Approach 2:
Specific local modifications are made to the furin cleavage site region (e.g., mutating RXXR to RXG or AXXA) to prevent cleavage, while other regions of the prodomain remain intact to maintain growth factor binding and signaling modulation functions.
2Reliability
If growth factors are tightly sequestered in latent form, then signaling is controlled, but cellular activity modulation is limited
Solution Approach 1:
The system transitions from static latent storage to dynamic controlled release. Recombinant proteins with modified cleavage sites provide dynamic control, allowing growth factors to be released in response to specific stimuli while maintaining the ability to modulate signaling pathways through regulated interactions with cell surface receptors.
Solution Approach 2:
The modified prodomain acts as an intermediary that controls the transition between latent and active states. It mediates between tight sequestration and full activation, allowing regulated release and sustained signaling modulation through controlled interactions with extracellular matrix components and cell surface proteins.
Data Source
AI summary
Provided herein are proteins, antibodies, assays and methods useful for modulating growth factor levels and/or activities. In some embodiments, such growth factors are members of the TGF-β superfamily of proteins.