Signaling interplay between transforming growth factor-β receptor and PI3K/AKT pathways in cancer

• TGF-β receptor and PI3K/AKT pathways show diverse mechanisms of crosstalk.
• PI3K/AKT activation antagonizes the TGF-β/SMAD-induced cytostatic response.
• PI3K/AKT activation can convert tumor-suppressing into tumor promoting TGF-β function.
• TGF-β receptor and PI3K/AKT pathways cooperate in cancer progression.

The transforming growth factor (TGF)-β and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways are used in cells to control numerous responses, including proliferation, apoptosis, and migration. TGF-β is known for its cytostatic effects in premalignant states and its pro-oncogenic activity in advanced cancers. The pro-cell survival response exerted by growth-factor-mediated activation of PI3K/AKT has been linked to stimulation of tumor formation. Both TGF-β receptor and PI3K/AKT pathways were initially modeled as linear signaling conduits. Although early studies suggested that these two pathways might counteract each other in balancing cell survival, emerging evidence has uncovered multiple modes of intricate signal integration and obligate collaboration in driving cancer progression. These new insights provide the rationale for exploring their dual targeting in cancer.