AURKA phosphorylates PHLDA1

Stable Identifier
R-HSA-8853444
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Aurora kinase A (AURKA) phosphorylates PHLDA1 on serine residue S95. This residue is conserved in mouse and matches S98 in the recombinant mouse protein used for identification of the AURKA target site in PHLDA1. Although phosphorylation of AURKA on threonine residue T288 within the catalytic loop is needed for AURKA kinase activity (Walter et al. 2000), AURKA phosphorylation has not been specifically examined in the context of PHLDA1 phosphorylation and AURKA is therefore shown as unphosphorylated. AURKA-mediated phosphorylation promotes PHLDA1 ubiquitination by an unknown ubiquitin ligase, which triggers degradation of PHLDA1 and may contribute to the oncogenic role of AURKA in breast cancer. Unphosphorylated PHLDA1 contributes to AURKA ubiquitination and degradation but the identity of the ubiquitin ligase and cell cycle timing have not been determined (Johnson et al. 2011).

PHLDA1 is implicated as both a tumor suppressor and an oncogene. As a putative tumor suppressor, PHLDA1 may act by promoting cell death (Park et al. 1996, Neef et al. 2002, Hossain et al. 2003, Hayashida et al. 2006, Oberst et al. 2008) or inhibiting protein synthesis (Hinz et al. 2001). Higher levels of PHLDA1 in ERBB2 (HER2) positive breast tumors correlate with increased sensitivity to ERBB2 inhibitor, lapatinib (Li et al. 2014).

In estrogen receptor positive tumors, higher levels of PHLDA1 correlate with increased risk of cancer recurrence and distant metastases after hormone therapy, which may depend on the concomitant up-regulation of the NF-kappa B (NFKB) complex activity (Kastrati et al. 2015).

PHLDA1 has also been reported as a mediator of anti-apoptotic effect of IGF1 (Toyoshima et al. 2004). These studies suggest that PHLDA1 may have an oncogenic role in some settings.

Regulation of PHLDA1 expression has not been fully elucidated. PHLDA1 transcription may be directly stimulated by the activated estrogen receptor (Marchiori et al. 2008, Kastrati et al. 2015), possibly in cooperation with the NFKB complex (Kastrati et al. 2015). Indirectly, downregulation of microRNAs miR-181a and miR-181b in an estrogen and NFKB-dependent manner, increases stability of the PHLDA1 mRNA (Kastrati et al. 2015). Activation of ERK1 (MAPK3) or ERK2 (MAPK1) in response to ERBB2 or EGFR activation may also be involved in PHLDA1 up-regulation, possibly through a route that also involves JAK2 and STAT3 (Oberst et al. 2008, Li et al. 2014, Lyu et al. 2016). PHLDA1 may also be up-regulated in response to cellular stress such as heat shock (Hayashida et al. 2006), endoplasmic reticulum stress (Hossain et al. 2003) and oxidative stress (Park et al. 2013).

Literature References
PubMed ID Title Journal Year
21807936 PHLDA1 is a crucial negative regulator and effector of Aurora A kinase in breast cancer

Johnson, EO, Chang, KH, de Pablo, Y, Ghosh, S, Mehta, R, Badve, S, Shah, K

J. Cell. Sci. 2011
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
protein serine/threonine kinase activity of AURKA:PHLDA1 [cytosol]
Physical Entity
Activity
Orthologous Events
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Created