Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for...

Area of Science:

• Molecular Biology
• Cell Signaling
• Oncology

Background:

• The GLI code, comprising GLI protein functions, is central to Hedgehog (HH) signaling.
• GLI proteins exhibit context-dependent activities, with GLI1 often acting as an activator and GLI3 as a repressor.
• GLI activity is modulated by co-factors, structural modifications, and diverse signaling pathways beyond HH.

Purpose of the Study:

• To review the regulation of the GLI code by both canonical HH signaling and non-canonical inputs.
• To explore the concept of 'oncogenic load' and its role in shifting the GLI code towards activating states in cancer.
• To highlight the context-dependency of GLI action and signaling integration, including HH and EGF pathways.

Main Methods:

• This review synthesizes existing literature on GLI protein function and regulation.
• It integrates concepts of signaling pathways, oncogenic mutations, and tumor suppressor activity.
• The review discusses the balance between GLI activating (GLI(A)) and GLI repressing (GLI(R)) states.

Main Results:

• The GLI code is influenced by multiple signaling inputs, impacting proto-oncogenes and tumor suppressors.
• In cancer, oncogenic load disrupts the GLI code balance, favoring activating states.
• Elevated GLI(A) levels are linked to advanced malignant stages.

Conclusions:

• Understanding the GLI code, oncogenic load, and context-dependent GLI action is crucial.
• Targeting the GLI code offers therapeutic potential beyond blocking individual pathways.
• Restoring the balance of GLI(A) and GLI(R) states may be a key therapeutic strategy in cancer.