Abstract
Peptidyl prolyl isomerases (PPIases) are broadly expressed enzymes that accelerate the cis-trans isomerization of proline peptide bonds. The most extensively studied PPIase family member is protein interacting with never in mitosis A1 (PIN1), which isomerizes phosphorylated serine/threonine–proline bonds. By catalyzing this specific cis-trans isomerization, PIN1 can alter the structure of its target proteins and modulate their activities in a number of different ways. Many proteins are targets of proline-directed phosphorylation and thus PIN1-mediated isomerization of proline bonds represents an important step in the regulation of a variety of cellular mechanisms. Numerous other proteins in addition to PIN1 are endowed with PPIase activity. These include other members of the parvulin family to which PIN1 belongs, such as PIN4, as well as several cyclophilins and FK506-binding proteins. Unlike PIN1, however, these other PPIases do not isomerize phosphorylated serine/threonine–proline bonds and have different substrate specificities. PIN1 and other PPIases are overexpressed in many types of cancer and have been implicated in various oncogenic processes. This review will discuss studies providing evidence for multiple roles of PIN1 and other PPIases in glioblastoma and medulloblastoma, the most frequent adult and pediatric primary brain tumors.
Highlights
Peptidyl prolyl isomerases (PPIases) are broadly expressed enzymes that accelerate the cis-trans isomerization of proline peptide bonds
protein interacting with never in mitosis A1 (PIN1)-mediated peptidyl prolyl cis-trans isomerization usually leads to conformational changes in the target protein that can result in modifications of its biological properties, including catalytic activity, stability, protein–protein interaction ability, and binding to DNA or RNA, depending on the particular substrate
The first suggestion that at least some members of the cyclophilin family might be involved in gliomagenesis came from the observation that expression of cyclophilin A (CypA) is elevated in human glioblastoma cell lines and tissues when compared to normal astrocytes and control brain tissue [59,60]
Summary
Dysregulation of proline-directed phosphorylation mechanisms mediated by protein kinases such as MAPKs, CDKs, glycogen synthase kinase 3, and polo-like kinases (PLKs), to name a few, is a common event in cancer [1,2,15,16]. Given the important role played by PIN1 in regulating the functions of substrates of proline-directed phosphorylation, it is not surprising that deregulated PIN1 expression or activity has been associated with numerous cancers (previously reviewed in [17,18,19,20,21]). Several additional mechanisms are believed to underlie the involvement of PIN1 in the development of multiple cancers, including the regulation of numerous transcription factors responsive to growth-inducing signals. These and other processes have been reviewed previously (e.g., [17,18,19,20,21,22]) and will not be addressed in detail here. This review will focus on the involvement of PIN1, as well as other PPIases, in glioblastoma and medulloblastoma, the most frequent adult and pediatric primary brain tumors, respectively
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