Associate editor: P. DentPIM kinase (and Akt) biology and signaling in tumors
Introduction
Solid and hematopoietic cancers utilize intercellular signaling cascades mediated by oncogenic kinases to maintain tumor cell growth and survival. In normal cells, the activity of these kinases is tightly controlled, whereas their sustained activation promotes apoptotic resistance and uncontrolled proliferation. PIM and Akt are serine/threonine kinases that are frequently activated in human cancers, and they phosphorylate overlapping substrates to activate common pathways that control various physiological processes that ultimately dictate the balance between cell survival and apoptosis. As a result, these kinases represent promising targets for cancer therapy and they are the focus of intense drug development efforts. Understanding how these kinases control distinct and overlapping signal transduction pathways is important for designing rational drug combinations and improving the efficacy of PIM and Akt inhibitors in the clinic.
The Proviral Integration site for Moloney murine leukemia virus (PIM) kinases were initially discovered through a viral-insertion screen for genes that enhance the development of lymphoma in the Eu-myc tumor model. The PIM family of serine/threonine kinases consists of three isoforms (PIM1, PIM2, and PIM3) that are highly conserved throughout evolution (Nawijn et al., 2011). Separate genes located on different human chromosomes encode the PIM isoforms, and they share high sequence homology at the amino acid level; PIM1 and PIM2 are 61% identical and PIM1 and PIM3 are 71% identical (Baytel et al., 1998). Multiple reports have demonstrated functional redundancy between PIM kinase isoforms both in vitro and in vivo (Mikkers et al., 2004, Bullock et al., 2005, Narlik-Grassow et al., 2012). Alternative translation initiation sites have been described for PIM1 and PIM2, giving rise to isoforms with different molecular weights. The PIM1 kinase encodes 33 and 44 kDa isoforms that display comparable kinase activity (Saris et al., 1991). However, the longer isoform of PIM1 was demonstrated to bind to the SH3 domain of the ETK/BMX tyrosine kinase, localizing it to the plasma membrane, whereas the shorter isoform is primarily localized in the cytosol and nucleus (Xie et al., 2006). PIM2 exists as three isoforms (34, 37, and 40 kDa), but no differences in protein function or interaction have been described. PIM3 has only been described as a single isoform (Nawijn et al., 2011). The PIM kinase isoforms are ubiquitously expressed, although some tissue specificity has been described: PIM1 is highly expressed in hematopoietic cells, gastric, head and neck, and prostate tumors (Bachmann et al., 2006, Cibull et al., 2006); PIM2 is highly expressed in lymphoid and brain tissues (Cohen et al., 2004, Mikkers et al., 2004); and PIM3 is highly expressed in breast, kidney and brain tissues (Feldman et al., 1998). In contrast to a majority of serine/threonine kinases, including Akt, the activity of PIM kinases is not regulated by cellular localization or post-translational modification. X-ray crystallography structural analyses of PIM1 revealed that this protein contains a conserved catalytic domain but lacks a regulatory domain (Qian et al., 2005). Therefore, it is thought that PIM kinases are constitutively active when expressed in cells, and their activity is directly correlated with their expression level.
The PKB/Akt family of serine/threonine protein kinases play a central role in signaling downstream of phosphatidylinositol 3-kinase (PI3K) (Cantley, 2002). The Akt gene was originally discovered as a transforming retrovirus isolated from the AKR mouse strain, which spontaneously developed many types of cancer. Subsequently, the oncogene encoding this virus was discovered and termed v-Akt. Thus, the later identified human analogues were named accordingly (Staal, 1987). Akt is a member of the AGC kinase family, which mediate a wide array of important cellular functions, and whose dysregulation is strongly associated with the pathogenesis of many human diseases, most notably cancer (Pearce et al., 2010). The activation of Akt is controlled by phosphorylation at two conserved residues known as the activation loop, which is controlled by the upstream kinase PDK-1 (phosphoinositide dependent kinase-1) (Toker & Newton, 2000), and the hydrophobic motif, which is regulated by the mTORC2 complex (Sarbassov et al., 2005a, Sarbassov et al., 2005b), as well as other kinases (Warfel et al., 2011, Xie et al., 2011); phosphorylation at both of these sites is necessary maximal activation of the enzyme. Once activated, Akt phosphorylates defined substrates throughout the cell, ultimately inducing pro-proliferation and anti-apoptotic signaling pathways (Cantley, 2002). The structure and function of Akt have been reviewed in great detail (see Vivanco and Sawyers, 2002, Hanada et al., 2004).
Section snippets
Transcriptional regulation
The expression of PIM kinases is largely regulated at the transcriptional level. The PIM kinases are downstream of multiple oncogenic tyrosine kinase receptors, including Janus kinase (JAK) (Wernig et al., 2008) and FMS-like tyrosine kinase 3 (FLT3) (Kim et al., 2005). The JAK/STAT pathway plays a critical role in regulating the expression of PIM genes. The JAK/STAT pathway represents an alternative to the second messenger signaling system, which is required for the activation of Akt, PKC, and
Proviral integration site for Moloney murine leukemia virus and protein kinase B kinase signaling in cancer
An investigation of the amino acid sequence specificity of PIM1 substrates revealed that PIM1 prefers to phosphorylate peptides with the following motif: K/R–X–X–X–S/T–X (X is neither a basic group nor a large hydrophobic residue) (Friedmann et al., 1992). Further screening of peptide libraries identified the consensus sequence that bound to PIM kinases, ARKRRRHPSGPPTA (termed “pimtide”) (Bullock et al., 2005). Notably, this consensus phosphorylation motif is strikingly similar to that of Akt
Proviral Integrations of Moloney virus kinases promote carcinogenesis
Anton Berns and colleagues originally identified the pim1 gene as an integration site of the Moloney murine leukemia virus during a screen of viral carcinogenesis (Selten et al., 1984), and all three PIM isoforms were identified as genes co-activated with myc in murine lymphoid tumors (Nawijn et al., 2011). The Pim kinases are overexpressed in a wide variety of human tumors of both hematological and epithelial origin. PIM1 expression is correlated with tumor aggressiveness, and it is a marker
Summary and perspectives
In many tumor types, prosurvival kinases represent a sought after target for drug development. While the PI3K/Akt pathway inhibitors have been validated in preclinical and clinical trials, resistance remains a major obstacle to their effective use. Based on their activity in the cell cycle and apoptosis, their frequent overexpression in cancer and their association with enhanced tumor growth and chemoresistance, the PIM kinases represent a promising target for anticancer drug discovery. As PIM
Conflict of interest
The authors disclose no conflicts of interest.
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