TTP

THROMBOTIC THROMBOCYTOPENIC PURPURA (HYPOTHESIS CONTINUES)

Here is the example of a metastatic mechanism going bad when it hits the right ADAM.  Remember that ADAM are made of 2 basic domains, one an integrin and one a metalloproteinase domain.  The Metalloproteinase enters the Flippase-floppase (or sometimes scramblase)-like structure and is destined to be rejected outside, the Integrin is sent inside the cell.
Metalloproteinases are sent outside and attack collagen-like molecules to open the way to cell migration and allow Metastatic processes to move forward.  However, the cell membranes have a collagen-like structure, too.  So potentially the released Metalloproteinases could attack the cell.  The cell is not stupid and knows what metalloproteinase it has put out.  So it shields itself with Inhibitors and Decoy receptors from that specific metalloproteinase and the cell goes about its migration.

2 conclusions:

1. Insufficient inhibitors and decoy receptors to Metalloproteinases (and others such as Hydroeicosatetraenoic Acid) will have devastating effects.  If genetically the inhibitors are insufficient, and metalloproteinases are expressed massively, and this happens at the endothelial cell, massive and extensive destruction of endothelial cells throughout the body happens, exposing collagen like structures of the blood vessel walls.  This of course trigger extensive activation of platelets and the Thrombosis of TTP-like syndrome.  So in TTP, it is the inhibitor that is lacking.  (ie Von Willebrand cleaving protease inhibitors have also been cited).  And plasmapheresis removes the the Metalloproteinases (and microbial Antigens/toxin when relevent), stopping the onslaught.

2.What is in the Integrin domain is critical, in ADAM-17, the integrin domain is occupied by TNF-alpha, converting enzyme (TACE) which will free and activate the devastating Tumor Necrosis Factor.  Released massively, TNF can not only induce Apoptosis like certain other Cyclins (interleukine and Interferon ), but also leads directly to NECROSIS.  A massive uncontrolled septic-like syndrome kills rats after infusion of TNF.

ADAM 10, the disintegrin there gives you Amyloid structures of Alzheimer's.  TO BE SHORT, PICK THE ADAM AND SEE THE CONSEQUENT DISEASE ON YOUR OWN!

ADAM! A FLIPPASE, FLOPPASE AND/OR A SCRAMBLASE-LIKE MOLECULE !

LBK1, A CONFUSING MARKER OF CANCER
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In lung cancer, Harvard researchers have pushed us now to request a lengthy list of Markers in order to direct our treatment.  The many options of therapeutic interventions have to be selected more sharply as new Driver mutations are discovered and new Target therapy drugs are made available.  We made a summary of drugs and their relevant Driver Mutations in our previous blog. (KRAS, EGFR, ALK, HER-2, BRAF, ROS-1,RET, MEK-1,NRAS, MET etc. for Driver Mutations.....Medications included Erlotinib, Gefitinib, Herceptin, Lapatinib, Veramufenib, Cabozantinib, Crizotinib etc. - SEE OUR BLOG)

But for a while, 5 Mutations were mostly adopted: KRAS, BRAF, EGFR, ALK and LBK1.
The surprise choice of LBK1 has remained somewhat of a confusion. Because no one knows what to do with the information despite the fact that we know a bit about the gene.  In these days, any Mutation or suppressed gene is suspect and prognosis conclusions are down. Presence of Mutation at LBK1 is considered of poor prognosis.  But wait a second! Let me shake a bit this notion:

Where do we find LBK1 alteration?

In DCIS
and In Polyps
and in Hamartomas ( Peutz Jeggers) : These do not sound like invasive cancers to me!

The DCIS case: Clinicians have maintained that DCIS do not invade, and Lymph node biopsy is generally not performed in case of DCIS.  Malignant transformation occurs here at 1% a year.  So we need additional Mutations for DCIS to adopt a cancerous profile.

In Peuts Jeggers, despite the presence of LBK1 (STK-1), polyps take their time to transform.  There the patient could develop pancreatic cancers for sure, but only after additional mutated genes come to bear! And the likelihood of this is high since a number of known substrates have been recognized to interact with LBK1.

Through Wikipedia:

SUBSTRATES OF LBK1 INCLUDE:

1.   BRSK 1&2 --------Through these substrate, it insure Neuronal Polarity.  And control length of neurons.
                       I should come to cellular polarity in a bit!  But here also comes its power to organize Microtubules and could have implications on resistance vs sensitivity to Taxanes!

2.  MARK 1&2--------This is where it controls Apico-basal cell Polarity, it may be controlling the      popular topic of Flippase, Floppase and Scramblase.

3.  SIK 1,2 : Through this substrate and its co-activator TORC2, LBK1 finds its inhibitory effect on Gluconeogesis.

4. AMPK signal pathways which favor proteins formation and translation while blocking lipogenesis.  Metabolically, it favors Catalysis with generation of ATP while blocking reactions requiring consumption of ATP.  At the cellular membrane the exchange of phosphorylated groups drive GTPase.  Putting LBK1 center to pathways activation.  At the Mitochondrial Membrane this has even more of an impact.

5.  NUAK  1,&2  which regulate Apoptosis through P53.  It is speculated that the overall effect of LBK1 is naturally anti-tumor.  Its alteration stops Apoptosis.

6. In the Embryo, LBK1 has demonstrated a role in Angiogenesis.   MEK or VEGF interaction is assumed.

One speculated that chronic exposure to Insulin like growth factor stimulation, or Estrogenic stimulation or inflammation or chronic mechanical stimulation forces desensitization through SPRADD or other genes altering LBK1 leading to loss of polarity and linear arrangement of cells by dysfunctional adhesion leading to "benign tumorous formations called polyps.  Further alterations happen as abnormal genetic evolution occurs and progresses into a full blown Malignancy.

It is also believed that once malignant transformation happens, LBK1 functions could "amplify" then the transformation favoring cell migration.

Many questions remain to be solved when it comes to LBK1...

FLIPPASE, FLOPPASE, SCRAMBLASE

One of nature's secret and ability to hide it, is by being simple.  While we expect things to be complicated and full of contorsions,  we are startled when at the end what we find is simple to understand!  One of the things we had figured out to be simple is the role of flippase and floppase, and may be the role of scramblase.   If one looks at a battery we use to power small electric equipment, one side is positive, the other is negative.  So there is a positive pole and a negative pole.  We can conclude that the battery is polarized.  The limit of a cell or one way the cell keeps what is inside of it, is by having its membrane polarized like an electrical fence.  The cell has understood that to be electrically polarized you got to have molecules in the membranes full of electrons.   And these electron-filled-molecules need to be maintained in position no matter what !  So the cell figures we need some Flippases and floppases to put things in the order above.  Meaning if the molecules we need in position A is outside the cell in position B, flip it in the right position A no matter what.  While flippase go A to B bringing these molecule inside.  Floppase goes B to A, sending molecule outside.  The Scramblase does both functions to mix things up!

This seems simple enough but wait!
This is how the cell tells the other cell "I am a dead cell, get rid of me"
Indeed, dead cells move Phosphatidyl serine, a normally internal surface molecule, to the outside of the cell, making it one of the most powerful signals to the Macrophage that this cell needs to be attacked and removed.
This disruption in lipid molecules is also linked to Bleb formation in the membrane, another powerful sign of cell death.   It is related to Caspase activity as an inducer of death, and therefore it is related to our 2nd law of nature which induces Caspases.  YOU CAN SEE HOW SIMPLE THINGS GET COMPLICATED FAST!  (This is also linked to protein Kinase activation, by the way!)
QUESTION NOW: ARE FLIPPASE AND SCRAMBLASE TARGET FOR THERAPY?  You better believe it.

We are working hard at CRBCM, but CPRIT is resisting with the help!  Please help us!

NOTE   A is inside the cell
              B is outside the Cell, in our example.