PTEN Dual Lipid- and Protein-Phosphatase Function in Tumor Progression

Abstract

PTEN is the second most highly mutated tumor suppressor in cancer, following only p53. The PTEN protein functions as a phosphatase with lipid- and protein-phosphatase activity. PTEN-lipid-phosphatase activity dephosphorylates PIP3 to form PIP2, and it then antagonizes PI3K and blocks the activation of AKT, while its protein-phosphatase activity dephosphorylates different protein substrates and plays various roles in tumorigenesis. Here, we review the PTEN mutations and protein-phosphatase substrates in tumorigenesis and metastasis. Our purpose is to clarify how PTEN protein phosphatase contributes to its tumor-suppressive functions through PI3K-independent activities.

Keywords: PTEN; PTEN lipid phosphatase; PTEN protein phosphatase; PTEN protein substrate; metastasis; mutation; tumorigenesis.

Figure 1

Schematic of the PTEN protein. (A) PTEN contains five functional domains: two key domains that are required for its tumor-suppressor function: the phosphatase (catalytic) domain (amino acids 14–189), with an active site included within the residues 123 and 130 (black), and the C2 (lipid-membrane-binding) domain (amino acids 190–350) (red); two binding domains that are the N-terminal PIP2-binding domain PBD (amino acids 1–14) and C-terminal PDZ-binding domain (grey; amino acids 401–403), which binds proteins containing PDZ domains; the carboxy-terminal region (amino acids 351–400), which contains PEST sequences and contributes to PTEN stability and activity, and is less well defined in the tumor-suppressor functions of PTEN. Wild-type PTEN with both lipid- and protein-phosphatase activity inhibits the cell cycle, AKT activity, and cell migration. The mutation at C124S (∆LP) inactivates both PTEN lipid and protein phosphatase, which provokes the loss of the inhibition of cell-cycle arrest and AKT and cell migration. The G129E (∆L) mutant loses only its lipid-phosphatase activity and can still inhibit cell migration. The mutation of Y138L is deficient in its protein phosphatase, which may lose the capacity to inhibit cell migration. (B) Three PTEN alternative translational isoforms, PTENα, PTENβ, and PTENε, which are produced from the same mRNA as canonical PTEN and are generated due to non-AUG translational initiation. Each has a longer N-terminal extension than the canonical PTEN protein.

Figure 2

PTEN has four major cellular functions. By dephosphorylating PIP3 and negatively regulating the activation of AKT, PTEN can both prevent the activation of Bcl2 and GSK-3 and promote the activation of caspase, thereby inducing cell apoptosis (1), and against both the AKT and MAPK signaling pathways to promote cell-cycle arrest (2). The protein phosphatase dephosphorylates the FAK proteins to reduce cell adhesion, movement, and migration (3). It can also shuttle into the nucleus to maintain genomic integrity (4).

Figure 3

PTEN functions as a haploinsufficient tumor suppressor. PTEN loss correlates with the incidence of tumorigenesis and increased activity of AKT in a dose-dependent manner (the more loss of PTEN (left panel), the higher tumor incidence (middle panel) and AKT activity (right panel)). PTEN deficiency (0% of PTEN) leads to embryonic lethality and hyperactivated AKT, while the hypomorphic allelic loss of PTEN (Hypo 30%) revealed more increased cancer phenotypes than the heterozygous loss of a PTEN allele (Het 50%) and the hypermorphic allelic loss of PTEN (Hyper 80%, with small 20% reductions in PTEN doses) (the tumor incidence from high to low: Hypo 30% > Het 50% > Hyper 80%). In contrast, elevated PTEN (>100%) protects against tumorigenesis and promotes longevity in GEM models [23,24,25].

Figure 4

PTEN mutations cause PTEN inactivation and loss of the tumor-suppressive function. Most PTEN mutations in cancer (TCGA dataset) are found in its phosphatase domain, including G129, Y138, C124, and R130, which lose lipid or protein or both phosphatase activities.

Figure 5

The function of PTEN can be regulated by different mechanisms through various genes, including transcriptional regulation, post-transcriptional regulation, epigenetic regulation, and posttranslational modifications. The transcriptional downregulation of PTEN causes protein levels to decrease by epigenetic regulation (promoter methylation) transcriptional factors.