Morgana is a ubiquitously-expressed protein essential for mouse and Drosophila development, able to regulate centrosome duplication and to maintain genomic stability1.
Morgana belongs to the CHORD containing protein family, since it contains two CHORD (Cysteine and Histidine rich) domains located at its N-terminal. These domains are phylogenetically conserved from plants to mammals2 and mediate the interaction with other proteins, among them the chaperone protein HSP903 and the Rho-dependent kinases ROCKI and II1, 4. Morgana is also characterized by the presence of a CS (typical of CHORD and SGT1 proteins) domain2 at its C-terminal.
The known Morgana binding partners are listed in the table below.
IP: co-immunoprecipitation
PD: pull down
TH: two-hybrid system
fW: far Western
MS: mass spectrometry
From a molecular point of view, Morgana acts at the crossroad of different signal transduction pathways, acting as an Hsp90 co-chaperone, binding to and inhibiting Rho kinases I and II1, 4 and activating NF-κB5.
Hsp90
Different stress stimuli provoke unfolded proteins accumulation leading to cellular damage and death. Chaperone proteins, by inducing protein refolding, directing denatured proteins to degradation and inhibiting unfolded protein aggregation, are of crucial importance in limiting cellular damage and enhancing cell survival. Morgana binds to Hsp90, a well-known chaperone that, in association with a number of different co-chaperones, assists several target proteins (Hsp90 clients) during folding and conformational changes required for their function. Morgana behaves as an Hsp90 co-chaperone, but it also displays an HSP90-independent molecular chaperone activity in suppressing the aggregation of denatured proteins.
ROCK I and II
Morgana binds to Rho kinases ROCKI and ROCKII, two multifunctional proteins acting downstream of Rho GTPases and involved in regulating cell morphology, cell adhesion and motility, cell proliferation, differentiation, apoptosis and oncogenic transformation6. We demonstrated that Morgana inhibits ROCKI and II in different cell types1, 4.
Centrosomes
The kinase activity of ROCKII is required for centrosome duplication and constitutively active mutants of ROCKII cause centrosome amplification7. In S phase, nucleophosmin (NPM) activates ROCK II, inducing centrosome duplication. Morgana interferes with the ability of NPM to activate ROCK II, negatively regulating ROCKII kinase activity and suppressing centrosome overduplication1.
Apoptosis
Morgana overexpression transforms NIH3T3 mouse fibroblasts and increases MCF7 breast cancer cells oncogenic properties4. High Morgana levels enhance the ability of cells to withstand diverse apoptotic stimuli such as serum withdrawal, anoikis and treatment with chemotherapic drugs. ROCK I phosphorylates and stabilizes PTEN that, in turn, counteracts PI3K signaling and AKT activation. High Morgana expression levels, resulting in decreased ROCK I activity, cause reduced PTEN stability, increased AKT activation and resistance to apoptosis4.
NF-κB
We demonstrated that Morgana associates to the mature IKK complex and that Morgana overexpression is sufficient to activate NF-κB in primary and cancer cells and to drive cancer progression5. Our data indicate that Morgana is required to connect the IKK complex to IkBa, promoting its phosphorylation and leading to NF-κB activation5.
Morgana behaves both as an oncosuppressor and as a proto-oncogene depending on its expression levels and on the specific cellular context. Low Morgana expression levels, by inducing ROCK hyperactivation, cause centrosome overduplication followed by genomic instability and induce proliferation in specific cell types, like myeloid cells. On the other hand, Morgana overexpression induces tumor cell survival, chemoresistance and cancer progression through the ROCK I-PTEN-AKT axis and the activation of the NF-κB pathway.
Hematological tumors
ROCK activation represents an important proliferative signal in myeloid cells8, 9 and Morgana, by regulating ROCK activity, specifically impact on the myeloid lineage. Mice heterozygous for morgana coding gene null mutation (morgana +/- mice) spontaneously develop a lethal myeloproliferative disease resembling human atypical chronic myeloid leukemia (aCML), preceded by ROCK hyperactivation, centrosome amplification, and cytogenetic abnormalities in the bone marrow. Accordingly, bone marrow (BM) from patients affected by aCML, showed a marked Morgana underexpression10.
Solid tumors
Morgana is overexpressed in a subset of human breast cancers4, correlating with metastasis formation and poor prognosis5. We found that high Morgana expression levels confer pro-survival abilities and chemoresistance to breast cancer cells4 and we defined an essential role for Morgana in tumor growth and metastasis formation in pre-clinical models of breast cancer5. In particular, high Morgana expression levels in cancer cells decrease NK cell recruitment in the first phases of tumor growth, while, later, it induces neutrophil colonization of the primary tumor and of the pre-metastatic lungs, fueling cancer metastasis5.
