Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity

Abstract

Tumor angiogenesis, the formation of new blood vessels to support tumor growth and metastasis, is a complex process regulated by a multitude of signaling pathways. Dysregulation of signaling pathways involving protein kinases has been extensively studied, but the role of protein phosphatases in angiogenesis within the tumor microenvironment remains less explored. However, among angiogenic pathways, protein phosphatases play critical roles in modulating signaling cascades. This review provides a comprehensive overview of the involvement of protein phosphatases in tumor angiogenesis, highlighting their diverse functions and mechanisms of action. Protein phosphatases are key regulators of cellular signaling pathways by catalyzing the dephosphorylation of proteins, thereby modulating their activity and function. This review aims to assess the activity of the protein tyrosine phosphatases and serine/threonine phosphatases. These phosphatases exert their effects on angiogenic signaling pathways through various mechanisms, including direct dephosphorylation of angiogenic receptors and downstream signaling molecules. Moreover, protein phosphatases also crosstalk with other signaling pathways involved in angiogenesis, further emphasizing their significance in regulating tumor vascularization, including endothelial cell survival, sprouting, and vessel maturation. In conclusion, this review underscores the pivotal role of protein phosphatases in tumor angiogenesis and accentuate their potential as therapeutic targets for anti-angiogenic therapy in cancer.

Keywords: Ser/Thr phosphatases; Tyr phosphatases; endothelial cells; protein phosphatases; signaling pathways; tumor angiogenesis; tumor cells.

Figure 1

Different forms of vasculogenesis and tumor angiogenesis. (A) embryonic vasculogenesis; (B) sprouting angiogenesis; (C) intussusceptive angiogenesis; (D) tumor associated vasculogenesis; (E) vascular mimicry; (F)vascular co-option; (G) transdifferentiation of cancer stem cells.

Figure 2

Schematic representation of signaling pathways during tumor angiogenesis. Activation is indicated by pointed arrows, whereas flat arrows represent inhibition.

Figure 3

Schematic representation of the impact of PP1 on tumor angiogenesis via its substrates and interacting partners. Activation is indicated by green arrows, whereas inhibition is represented by red flat arrows.

Figure 4

Schematic representation of PP2A’s impact on tumor angiogenesis via its substrates and interacting partners. The figure depicts the PP2A holoenzyme, highlighting its three subunits: the scaffold subunit A, the regulatory subunit B, and the catalytic subunit C. Activation is indicated by green arrows, whereas inhibition is represented by red flat arrows.

Figure 5

Schematic representation of PPPs in tumor angiogenesis signaling pathways. Activation is indicated by pointed arrows, whereas flat arrows represent inhibition.

Figure 6

Schematic representation of VE-PTP signaling in tumor angiogenesis. Activation is indicated by pointed arrows, whereas red flat arrows represent inhibition.

Figure 7

Schematic representation of SHP-2 signaling in tumor angiogenesis.

Figure 8

Schematic representation of PTPs in tumor angiogenesis signaling pathways. Activation is indicated by pointed arrows, whereas flat arrows represent inhibition.