CASE IN POINT ABOUT FLIPPASE-FLOPPASE

Conceptually, most proteins of physiologic importance made in the cells are stored at the cellular membrane either as an integral part of the membrane called Integrins or anchored to it and in need of Secretases for secretion.
Most of the Integrins are attached to a Metalloproteinases (ADAMS10)
let say Epo, TNF,TGF  or Cyclin-D are attached to the membrane, with an cytoplasmic stimulation which liberates the TNF from its attachment, The TNF is" flipped" into the cell, and its related Metalloproteinase (2,9) is "Flopped" outside the cell.
The TNF will go on to influence epigenetic events such as increase transcription factors, The metalloprotease will go out to influence extracellular events.  Autoimmunes diseases that are associated with high Cytokines levels intracellularly, are also associated with high Metalloproteinnases extracellularly.  And cellular destruction of joint surfaces is in part due to Metalloproteinases doing their job of modifying the extracellular matrix in excess.
In sepsis for example, controlling the Metalloproteinases by a modified Tetracycline has proved to tamper the cellular attacks in this syndrome.
Remember not all proteins is attached to same Metalloproteinase since there are several class.  And all Metalloproteinases are not equal in what they do.  So it is important to inventory the Metalloproteinase by proteins to which they are attached, and to clearly major in each disease process which Metalloproteinase is increased.
Now because we are bound to secrete Metalloproteinase through the Flippase-Floppase process, our cells need to protect themselves from the Metalloproeinases they produce.  So each cell has anti-metalloproteinase "cover" to shield itself from its own production.  Lack of such protection lead to dangerous clotting events called TTP and HUD, events so dramatic that every Hematologist fear a call each time a patient present with low platelet!  The treatment is known, remove the Metalloproteases and other auto-antibodies through pharesis...
Yet Insurers will fight you if you want to know the level of Cytokines and their related Metalloproteinases.  No wonder that the NCI is calling for new Biomarkers in Autoimmune disease, opening the door for the future in Medicine...!